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Volume 4 Issue 3

Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

PEER REVIEWED

Brexit How NOAH is Working to Ensure a Thriving UK Animal Health Sector Data Protection An industry Success Story for New Zealand Agriculture Heat Detection in Dairy Cows A Review of Methods with an Emphasis on Those Using Milk How to Reduce Mycotoxin-induced Vaccination Failure

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CONTENTS 04 FOREWORD WATCH PAGES

Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker Project Director Clive Baigent, PhD Email: clive@iahjmedia.com EDITOR Maria Dominici maria@pharmapubs.com EDITORIAL ASSISTANT Virginia Toteva virginia@pharmapubs.com DESIGNER Jana Sukenikova www.fanahshapeless.com BUSINESS DEVELOPMENT Simon Wilkins Email: simon@iahjmedia.com ADMINISTRATOR Barbara Lasco FRONT COVER © istockphoto PUBLISHED BY Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 0207 237 2036 Fax: +0014802475316 Email: info@pharmapubs.com www.animalhealthmedia.com

06 A Year of Challenges and Progress The last year has been eventful. We’ve seen landmark moments in our international effort to tackle antimicrobial resistance, and Europe has been hit by some challenging animal diseases — most notably the ongoing bird flu outbreak which has swept across the continent. While there are a number of unprecedented challenges on the horizon, Nigel Paul Gibbens, CBE, Chief Veterinary Office (CVO) of the United Kingdom and for the Department for Environment, Food and Rural Affairs (DEFRA), talks optimistically about the important roles for the veterinary profession in the future and the ability to maintain a topclass reputation, including for expertise in surveillance and disease control. 08 Liver Fluke – An Impact on More than Welfare A particularly warm and wet start to summer in 2017 may result in a greater risk of liver fluke disease this autumn, meaning UK farmers must be ready to take action, says Rachel Mallet, Territory Manager at Bimeda. Fascioliasis is the name given to the disease caused by the liver fluke parasite, which may be caused by the migration of fluke through the liver tissue, causing damage, and the presence of the adult flukes in the bile duct; fascioliasis has a significant impact not only on the welfare of the stock but also on their productivity. REGULATORY & MARKETPLACE 10 Brexit: How NOAH is Working to Ensure a Thriving UK Animal Health Sector Following the result of the UK’s referendum on membership of the European Union, Dawn Howard, Chief Executive of NOAH (National Office of Animal Health), comments that the association is committed to working with the UK regulator, government and other stakeholder organisations on any forthcoming changes to regulations or market access conditions. It has been working hard towards the sector’s vison of an environment that delivers a thriving animal medicines sector post-Brexit, informing its members on the latest developments, and helping to steer a course through new legislation in discussions with UK politicians to get the best for animal health. 14

Veterinary Clinical Studies and Quality Assurance VICH GL9 GCP is the principle source of guidance for veterinary Good Clinical Practice (GCP) studies; it is from here we take our lead. Quality assurance (QA) in veterinary clinical studies is the responsibility of all study personnel as defined in VICH GL9 GCP. In the guidance, however, the role of quality assurance staff in veterinary clinical studies is illdefined. This article by Iain McPhee BSc, MBA, FRQA of RQA gives additional guidance on QA audit.

16

Data Protection – An Industry Success Story for New Zealand Agriculture Until recently, New Zealand had one of the worst data protection regimes for animal medicines in the developed world. This all changed in November 2016, when the parliament passed a major law change to extend data protection. The law change was a significant win for animal medicine and crop protection manufacturers, says Mark Ross, Chief Executive of Agcarm. At first the government was not interested in extending data protection – reasoning that it would be anti-competitive to generic-based companies, and would lead to product price increases for farmers; other drivers included agriculture’s critical role to New Zealand’s economy, and the need to incentivise less hazardous products and provide new and innovative products.

International Animal Health Journal – ISSN 1758-5678 is published quarterly by PHARMAPUBS.

The opinions and views expressed by the authors in this Journal are not necessarily those of the Editor, Publisher or the Supporting Organisations which appear on the front cover. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. Volume 4 Issue 3 September 2017 PHARMA PUBLICATIONS www.animalhealthmedia.com

International Animal Health Journal 1


CONTENTS 20

What Feed Statistics Tell Us about the Health of Animal Production and the World Economy In a global food chain, inputs such as animal feed reflect the overall health and evolution of both the industry and the economy at large. Changes in the demand for, and pricing of, animal feed reflect trends in consumer preferences, population growth, investment opportunities, economic development, animal husbandry and overall economic circumstances. In this article, Aidan Connolly, Chief Innovation Officer & Vice President, Corporate Accounts at Alltech, discusses the annual Global Feed Survey (GFS) report, which has become a bellwether of global economic trends, sometimes flagging changes before other indicators do. RESEARCH & DEVELOPMENT

24 Important Facts about Mycotoxins that Every Dairy Producer Should Be Aware Of The goal of the dairy farming industry is to supply dairy processing enterprises with high-quality milk that can be converted into highly-nutritious milk products for human consumption. Milk quality is determined by the composition of its nutrients and the level of contaminants or undesirable compounds. Therefore, every dairy farm aims to maximise the level of nutritious components and minimise the levels of contaminants in milk. Many factors on farms are known to influence milk quality. Radka Borutova, Business Development Manager at Nutriad International, explains how it is well established that many nutritional factors can contribute to the presence of contaminants and undesired compounds in the milk. 32 Epidemiology and its Application to Animal Health Health research is diverse and varied and covers a spectrum from basic research to applied research. The production of new therapeutic compounds, for example, begins at the laboratory bench (basic) and proceeds through rigorous testing in clinical settings (applied) before they can be widely used in regular practice. The purpose of this editorial, by Melissa Simpson, DVM, PhD, Veterinary Epidemiologist at Morris Animal Foundation, is to discuss details about the types of studies that fall under the umbrella of applied research, including their advantages and limitations, and their utility in advancing animal health. CLINICAL STUDIES 38 How to Reduce Mycotoxin-induced Vaccination Failure Immunotoxic substances such as mycotoxins are unsuspected players in the failure of vaccines to provoke a proper immune response. Vaccines are commonly used to prevent various pathogenic challenges of viral, bacterial, and protozoan origins that usually lead to diseases affecting health and performance of livestock. G. Raj Murugesan, Technical & Marketing Director and Erika Hendel, Swine Technical Manager at Biomin, give an insight into two major types of vaccines normally used in swine production and two different mechanisms involved in establishing an immune response. MANUFACTURING AND PACKAGING 40 Breakthrough Cell-based Companion Animal Therapies: New Treatments Bring New Challenges This article written by Kirk Randall, Sales Director at Cryoport, will address particular issues surrounding the logistics and shipment of cryogenic animal health products such as these new regenerative therapies, as they represent the highest level of need for any organisation working with these products. They also represent a higher level of resource needs for the end user where the shippers often end up serving as temporary storage units for the veterinary clinics treating their livestock with these critical stem cell 2 International Animal Health Journal

therapies for herd/flock health. The author will break the challenges into their core components and address solutions individually. LIVESTOCK 44 Dietary Strategies Protecting Heat-stressed Farm Animals against Increased Susceptibility to Inflammatory Diseases Global warming and the growing consumer demand for animal-derived food and meat, particularly in newlyindustrialising countries with hot climates, raise public concerns on animal welfare, long-term sustainable livestock production and food and consumer safety. In these areas, heat stress is one major reason for economic losses in livestock production. Tobias Aumiller, Xiaodan Zhou, Ester Vinyeta, Jan Dirk van der Klis, and Andreas S. Müller, of Delacon Biotechnik GmbH, explain that besides lowering the quality of forage and feedstuffs, a hot and humid climate reduces reproduction performance and productivity of livestock animals. Moreover, heat stress affects general health and the susceptibility of farm animals to infectious diseases. 50 Heat Detection in Dairy Cows: A Review of Methods with an Emphasis on those Utilising Milk The widespread global replacement of bulls with artificial insemination (AI) means that accurate detection and timing of oestrus becomes a critical activity. Traditional observation of behavioural signs have been re-evaluated, but these methods rely on regular visual observation of cows and an environment conducive to demonstration of oestrus behaviour. Dr Maggie Fisher BVetMed CBiol MSB MRQA DipEVPC MRCVS and Dr Peter Holdsworth AO FRSB FAICD, of Ridgeway Research Ltd, review some of the detection systems which have been commercialised and are widely adopted, whilst others remain in the research laboratory. SPECIAL FEATURE 56 HfA: Rabies Feature In this feature, HealthforAnimals Executive Director Carel du Marchie Sarvaas, talks through the target agreed by the World Health Organization, the World Organisation for Animal Health, the UN Food and Agriculture Organization and the Global Alliance for Rabies Control (which coordinates World Rabies Day), which is to reduce human deaths from canine rabies to zero by 2030. While many health professionals think of rabies as a problem of the past, the 2030 target highlights the devastating impact the disease still has in many parts of the world. Africa and Asia account for 99 per cent of human deaths from a disease that disproportionately impacts poor, rural communities. 60 UK Pet Population & Pet Food Market This piece by Nicole Paley, Communications Manager at PFMA, provides an insight into the Pet Food Manufacturers’ Association (PFMA), the principal trade body representing the UK pet food industry. Since 2008, PFMA has been tracking the UK pet population to provide robust data. This data is used by PFMA members and a wide range of bodies, including government departments, pet care businesses, welfare charities and the media. The data provides interesting facts and figures about all pet types – but it is also used to shape strategies and as such the quality and accuracy of this data is therefore critical.

Volume 4 Issue 3


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FOREWORD A very warm welcome to the Autumn issue of the Journal. This edition seems to have come around very quickly, possibly because of the earlier than usual disappearance of summer (at least in the UK). As usual, this issue is populated by high-quality articles dealing with a number of issues in a variety of topic (and topical) areas. So let’s have a look at a couple of these. Liver fluke infection (fascioliasis), caused by the common liver fluke, Fasciola hepatica, is a major parasitic disease of ruminants, and particularly of sheep and cattle. As the flukes pass through the liver tissues, they cause haemorrhage and liver enlargement and they leave behind them migratory tracts. In chronic cases, cirrhosis develops. They cause serious damage to the bile ducts that become enlarged and cystic, and develop fibrosed walls. Fluke has a worldwide distribution and it can lead to the deaths of sheep, although it may be asymptomatic in cattle. The life-cycle of the fluke is complex. Eggs pass from the infected animal and develop further until they enter the secondary host, the mud snail, where they develop further, emerge and encyst on plants such as grass, before being eaten by sheep or cattle to repeat the infection and the life-cycle. As the snail prefers muddy conditions, the incidence of fluke is higher in wet conditions, including those with poor drainage, and is greater in years when the summers are wet. It is, therefore, easy to see that liver fluke is a major animal welfare issue, and particularly for sheep, where the disease can be devastating. The disease can be treated but some therapeutic agents such as albendazole and oxyclozanide are only active against mature flukes, while closantel is active against slightly less mature flukes, and the drug of choice, triclabendazole, is active against immature and mature forms. However, there are reports of the development of drug resistance, including resistance against triclabendazole. The use of drugs to control fluke infections is only one of the economic costs of the disease. Production losses due to poor live weight gain, especially in sheep, are considerable; while in cattle, fluke-induced reductions in calving rates and milk yield are significant. Moreover, the liver pathology induced by flukes is not only important from a disease perspective, it can also lead to high liver condemnation rates at the abattoir. Rachel Mallet is a veterinarian working with Bimeda and in this issue of the Journal she discusses both the animal welfare and economic consequences of fascioliasis in farm animals.

Although liver fluke is all too familiar to farmers, to parasitologists and to veterinarians, it is not well known to the general public. This is despite the fact that fascioliasis is a zoonotic disease and can affect humans. Worldwide, there are a number of fluke species that can cause disease, animal welfare issues and economic losses, so it is timely that Rachel should review the issues involved. Lack of familiarity is not normally associated with rabies. The public are largely aware of the disease, know that it can be passed on by infected animals, especially dogs, and recognise that it is a very unpleasant disease that is usually fatal. However, many people, at least those living in Western Europe, would probably assume that it is a disease with very little impact on modern lives. Like polio and smallpox, it is a disease of the past. Unfortunately, and like polio, rabies is very much a continuing threat to health. According to the OIE, the World Organisation for Animal Health, half of the world’s population live in rabies-endemic areas, and rabies kills 60,000 people each year. It is estimated that 95% of human cases of rabies occur as a result of bites delivered by infected dogs. If only there were some tools available to deal with this situation… If treated promptly after being bitten, patients can survive a potential infection. Treatment with human rabies immunoglobulin followed by several administrations of rabies vaccine has been shown to be extremely effective as postexposure prophylaxis, but this is costly. A cheaper alternative is to vaccinate dogs (and reduce the numbers of stray animals). OIE estimates that by vaccinating 70% of dogs in endemic areas, canine rabies could be eradicated, which in turn would see the number of human infections fall to practically zero. This would be a huge step forward for both human and animal welfare but obviously, a clear strategy is required to achieve this objective. The OIE, working with the World Health Organisation (WHO), the Food and Agriculture Organisation (FAO) and the Global Alliance for Rabies Control has agreed a target to reduce human deaths from rabies in dogs to zero by 2030. This would be a magnificent achievement if realised. In this issue, HealthforAnimals Executive Director Carel du Marchie Sarvaas discusses this initiative. I hope you will enjoy reading these two articles about two very different but important diseases. However, I am confident that you will enjoy all of the other excellent contributions to the Journal.

Dr Kevin Woodward

Managing Director, KNW Animal Health Consulting

EDITORIAL ADVISORY BOARD Germán W. Graff Research Reference Laboratory Specialist, IDEXX BioResearch Fereshteh Barei - Health Economist & Strategy Advisor, Founder of BioNowin Santé Avenue Association Carel du Marchie Sarvaas Executive Director Health For Animals Kimberly H. Chappell - Senior Research Scientist & Companion Animal Product Development Elanco Animal Health Dr. Sam Al-Murrani - Chief Executive Officer Babylon Bioconsulting & Managing Director at Bimini LLC Sven Buckingham - Buckingham QA Consultancy Ltd. Dan Peizer - Director Animal Health at Catalent Pharma Solutions Dawn Howard - Chief Executive of the National Office of Animal Health (NOAH) Jean Szkotnicki - President of the Canadian Animal Health Institute (CAHI) Dr Kevin Woodward - Managing Director KNW Animal Health Consulting Norbert Mencke - VP Global Communications & Public Affairs Bayer Animal Health GmbH 4 International Animal Health Journal

Volume 4 Issue 3


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WATCH PAGES

A Year of Challenges and Progress

The last year has been eventful. We’ve seen landmark moments in our international effort to tackle antimicrobial resistance, and Europe has been hit by some challenging animal diseases – most notably the ongoing bird flu outbreak which has swept across the continent. While there are a number of unprecedented challenges on the horizon, I am very optimistic about the important roles for our profession in the future and our ability to maintain our top-class reputation, including for expertise in surveillance and disease control. Following the UK’s decision to leave the EU, it is now more important than ever to maintain the high standards we have achieved in the UK’s veterinary profession. We will look to our vets to continue the excellent work they do to emphasise the need for good welfare, biosecurity and vigilance to their clients, not only to protect their animals, but also the reputation of the UK itself. Our strong track record on animal welfare stretches back centuries, and the high standards we hold – reflected by the joint-highest score on the World Animal Protection Index – are a key part of our British food brand and our farmers’ offer to consumers. As a nation, we hold our animals’ welfare in high regard, and the UK has led the way to raise the bar, for example improving farm animal welfare by sow stalls and veal crates, and most recently banning battery cages for laying hens. Our vets are crucial to maintaining and improving the welfare of all kept animals, both farmed and companion. We are under constant threat from diseases exotic to the UK that can enter by a range of pathways, from smuggled animals or products to uncontrollable movements of wild birds or insect vectors. The UK has a strong track record of containing exotic disease when incursions do happen. This winter’s avian flu outbreak has tested our approach to disease control but, thanks in large part to the hard work and cooperation of vets and poultry keepers to identify early signs of disease and maintain good biosecurity, we have successfully kept disease spread to a minimum, particularly compared to other parts of Europe. As with any outbreak, we can always learn from our experiences and improve our response – and it is important to keep questioning how we could do better next time.

number of outbreaks of a disease which was previously unprecedented outside of Africa. It is an additional threat which we must monitor closely and be prepared for, should it reach our shores. Constantly working to improve the health of our animals will not only help to improve productivity and returns to farm businesses, along with the potential for exports, but will also help to reduce the need for antibiotics. The issue of antimicrobial resistance (AMR) was the focus for this year’s World Vet Day in April, and one that remains high on the global agenda. As vets, you are likely to find yourselves on the frontline of this fight. 2016 felt like a breakthrough year in our international efforts to tackle the growing problem of AMR. Lord O’Neill published his eagerly-awaited report on the topic, and the UK Government adopted his suggested ambitious targets to reduce antibiotic use in human and animal health. The UK took a leading role in securing a historic agreement at the UN General Assembly, with all 193 countries agreeing the need for action on antibiotic resistance. Most importantly, we saw real progress across the industry in implementing new practices to reduce the need for antibiotics. Defra’s latest report of sales of veterinary medicines showed sales of antibiotics for use in foodproducing animals dropped 10% between 2014 and 2015, continuing a ten-year downward trend and putting the UK well on track to meet Lord O’Neill’s target of 50mg/kg by the end of 2018. I am really pleased that, with the support of RUMA, our livestock sectors and their veterinary advisers have taken up the challenge of reducing antibiotic use further by making tailored improvements to management and disease control practices. But we must not rest on our laurels. There is still a lot to do and we have to keep pushing to ensure antibiotics are used responsibly and remain effective for future generations. We need to make progress on diagnostics, vaccines and management practices and better understand and mitigate risks from the environment. Science has an

Bluetongue virus (BTV-8) affected livestock across Europe last summer, but didn’t reach the UK. As the weather warms up this year, though, we must remain prepared as the risk increases again. Surveillance is being carried out in the UK, both in midges and in sentinel cattle. The impact of the disease in France appears low, but this may be different in previously unexposed animals in the UK. Farmers who think their herd could be at risk in the coming months, especially if they are of particularly high value, should talk to their vet about vaccination. Lumpy skin disease has never been present in the UK, but Europe has been challenged and shaken by a 6 International Animal Health Journal

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WATCH PAGES

important role to play. A world in which antibiotics are no longer an effective treatment option for people or animals is something we cannot allow to happen. Experts believe that, left unchecked, AMR could be directly responsible for 50 million deaths per year and cost the global economy $100 trillion by 2050. So the need for continued action, with the veterinary and medical professions working together in a One Health approach, is clear. The UK’s vets – both Official Veterinarians and those in the private sector – play a key role in protecting our country from endemic and exotic diseases, tackling outbreaks when they occur, safeguarding our animals and tackling global challenges like antibiotic resistance. Without your great work, we could not achieve our aims on animal welfare and would be in a poorer position to spot upcoming disease threats. It is absolutely vital that, as we move towards a new relationship with Europe and the rest of the world, we maintain and enhance our capabilities at home and continue to work with partners abroad. The Government’s commitment to high standards of animal health and welfare, coupled with the need to respond to the challenges and opportunities of leaving the EU, open up the possibility for a new strategic approach to securing good animal health and welfare and the benefits that will bring. The veterinary profession has an opportunity to help shape that future working with both animal keepers and the Government. www.animalhealthmedia.com

Nigel Gibbens Professor, the UK’s Chief Veterinary Officer. He was appointed in May 2008 following previous experience in the State Veterinary Service and in policy roles on international trade, BSE controls, animal welfare and international relations co-ordination for Defra’s Food and Farming Group. Prior to joining the UK government in 1990, Nigel worked in private practice in his early career and in government veterinary services in Belize and Yemen. Nigel enjoys cycling, walking at home and abroad, gardening and DIY. Nigel holds an Honorary Professorship from the Royal Veterinary College. He was appointed Commander of the Order of the British Empire (CBE) for services to the veterinary profession and animal welfare in the New Year’s Honours list for 2016. Email: nigel.gibbens@defra.gsi.gov.uk

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WATCH PAGES

Liver Fluke – An Impact on More than Welfare

A particularly warm and wet start to summer in 2017 may result in a greater risk of liver fluke disease this autumn, meaning UK farmers must be ready to take action. Fascioliasis is the name given to the disease caused by the liver fluke parasite. It may be caused by: • The migration of the fluke through the liver tissue, causing damage • The presence of the adult flukes in the bile duct Life Cycle

The cercariae burst out of the snail host after this period of development and migrate onto the herbage, where they encyst as metacercariae. These metacercariae are hardy and can remain viable for some time. The early immature fluke (one – five weeks old) tunnel through the liver tissue, eventually developing into the immature fluke. The immature fluke (six – nine weeks old) continue tunnelling towards the bile duct. Eventually they reach the bile duct and, if untreated at 10–12 weeks old, will mature into adults which produce eggs contaminating the pasture and continuing the life cycle. When are Livestock Affected? New infection occurs when the metacercariae are ingested from pasture. During very warm and wet summers, this could be as early as August. In cooler, dryer summers which do not favour the mud snail, there will be less metacercariae on the pasture and they will appear later. Existing infection, also known as chronic fluke disease, occurs when animals are harbouring flukes which were not treated after the new infection period. These flukes are then able to complete their life cycle into adults and reside inside the bile duct, producing eggs which contaminate the pasture. Chronic fluke disease is generally observed from January onwards.

Adult fluke inside the bile duct lays eggs which are passed out in the faeces on to the pasture. From the fluke releasing the egg until it reaches the pasture can be up to three weeks, due to the intermittent contraction of the bile duct. Once environmental conditions are optimum, the miracidium will develop inside the egg and then hatch out. This miracidium is only able to survive for a few hours after hatching out, so must find a snail host very quickly - the mud snail. If the miracidium is able to find a snail host, it will bury through its muscular foot where it undergoes a further two stages of development and multiplies, eventually becoming the infective cercariae. 8 International Animal Health Journal

Clinical Signs In late summer and early autumn, the risk period for acute fascioliasis begins. Acute fluke disease may result in the following: • • • • • • •

Sudden death Lethargy ‘Dullness’ Reduced feed intake Abdominal distension Abdominal pain Haemorrhage

If any stock die suddenly, always get a post-mortem carried out to avoid further loss. Impact on your Stock Fascioliasis has a significant impact, not only on the welfare of your stock but also on their productivity. Volume 4 Issue 3


WATCH PAGES Production consequences of liver fluke infection: • Reduced weight gain • Reduced food conversion ratio • Drop in milk yield • Drop in fertility • Death Liver fluke infection is estimated to cost UK farmers £300 million per year.1 In sheep, infection is estimated at £3–5 per animal, which comprises not only the cost of treatment but also the sub-clinical production losses such as reduced weight gain and liver condemnation.2 Liver fluke is estimated to cost producers £20–25 per head of cattle,3 resulting in a serious dent in profit margins. Treatment Liver fluke can be a challenging parasite to treat as different life stages are susceptible to different active ingredients and a reservoir of infection persists in the mud snail population and in the environment. Most importantly, in order to protect our flukicides from the development of resistance, you must select a product which targets only the life stages you are trying to kill and dose accurately. Your vet or SQP can advise you on the most appropriate product for your herd or flock. Key Treatment Points: • Use an active which targets only the life stages you are trying to kill • Remember that no flukicides prevent reinfection – if they are returned to the same pasture, reinfection will occur immediately • Weigh animals and dose accurately – under-dosing increases the rate of development of resistance Active Ingredient

Preparation

Age of Fluke Killed

Triclabendazole

Oral

Sheep – two days Cattle – two weeks

Pour-on

Cattle – six weeks+

Oral

Sheep – five weeks+

Injectable

Cattle – seven weeks+

Closantel

Sheep – seven weeks+

Nitroxynil

Pour-on

Cattle – seven weeks+

Injectable

Cattle – eight weeks+ Sheep – seven weeks+

Clorsulon

Injectable

Cattle - Adult

Oxyclozanide

Oral

Cattle - Adult Sheep -Adult

Albendazole

Oral

Cattle - Adult Sheep - Adult

Table 1: Active ingredients licensed for fluke treatment in sheep and cattle www.animalhealthmedia.com

Prevention New animals entering the farm may act as a source of infection. Ensure that you have good biosecurity protocols in place. Chronically infected animals will contaminate the pasture when let out to grazing in spring - check if stock are affected in spring with a faecal sample and treat if necessary. Environmental controls such as drainage, fencing off wet areas and moving animals from high-risk pasture at key times can greatly reduce the number of metacercariae ingested and subsequently the severity of disease. Liver fluke control should also be incorporated into your herd and flock health plans. REFERENCES 1. Control of Worms Sustainably Liver Fluke Technical Manual http://www.cattleparasites.org.uk/guidance/manual/ COWS%20Controlling%20liver%20and%20rumen%20 fluke%20in%20cattle.pdf 2. EBLEX (2013) Economic impact of health & welfare issues in beef cattle and sheep in England. http://beefandlamb. ahdb.org.uk/wp/wp-content/uploads/2013/04/EconomicImpact-of-Health-Welfare-Final-Rpt-170413.pdf 3. Feedback to Farmers- Controlling Liver Fluke http://www.qmscotland.co.uk/sites/default/files/ Added%2BValue%2BTopic%2B4%2BLiver%2BFluke.pdf

Rachel Mallet A qualified Veterinary Surgeon, who now works as a Territory Manager for Bimeda, covering accounts in Scotland and the North of England. Rachel is passionate about animal health and about promoting best practice amongst farmers and animal owners. Email: rmallet@bimeda.com

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REGULATORY & MARKETPLACE

Brexit: How NOAH is Working to Ensure a Thriving UK Animal Health Sector Following the result of the UK’s referendum on membership of the European Union on 23 June 2016, Dawn Howard, Chief Executive of NOAH (National Office of Animal Health) commented that the association was committed to working with the UK regulator, government and other stakeholder organisations on any forthcoming changes to regulations or market access conditions. Never a truer word: she also said it was clear the process of leaving the EU was not clear and that this will be a lengthy process of negotiations. Over a year on from the vote, a new UK prime minister and a general election later, and a quarter of the way into the two-year period of negotiation post-trigger of Article 50, the clock is ticking but there is no further clarity on how the Brexit process will evolve. As the trade association representing the UK animal medicines industry, NOAH has been working hard towards the sector’s vison of an environment that delivers a thriving animal medicines sector post-Brexit, informing its members on the latest developments, and helping to steer a course through new legislation in discussions with UK politicians to get the best for animal health. The UK’s future relationship with the EU and access to the single market will be critical. To agree strategy, the NOAH Board of Management established a Brexit Task Force, with representation from companies headquartered in the UK and overseas (in and outside the EU), with UK manufacturing and without, and across the regulatory/ commercial spectrum. They set a vision of an environment that delivers a thriving animal medicines sector: • Supporting trade and innovation • Safeguarding animal health and welfare and public health and food safety; ensuring that UK veterinarians and animal keepers continue to have access to a wide range of appropriate veterinary medicines • Businesses have access to skilled staff – the right workforce they need • Product research and development is incentivised within a regulatory system which continues to be one of the most stringent in the world – making the UK the first choice world-leading regulatory authority • Companies are encouraged to do business in the UK as unnecessary regulatory burdens are recognised and removed • Transitional arrangements to support business continuity post-EU exit are built, utilising links with specialist EU infrastructure where necessary They developed a paper1 that examined what was needed in relation to regulatory challenges and future regulatory models. Veterinary medicines are, quite rightly, heavily regulated to protect animals, people and the environment. The UK 10 International Animal Health Journal

regulator, the Veterinary Medicines Directorate (VMD) is considered to be a lead regulatory agency across Europe. In 2015, the UK acted as Reference Member State in 43% of EU mutual recognition procedures, being the lead regulatory agency for 73 out of 168 applications. Keeping regulatory efficiencies Where veterinary medicines work on EU applications for marketing authorisations has been carried out by one or two EU countries, then recognised by the others, there are efficiencies and reduced resource needs for UK businesses and regulators alike. The UK needs continued access to this system to avoid duplication of work and extra resource, as well as to the existing EU infrastructure such as electronic submission portals and databases that provide efficiencies and cost savings to both regulators and industry. Ensuring UK availability of new medicines A business’s decision to develop a new veterinary medicine is often made on a regional basis, i.e. a treatment for a disease occurring in a number of countries where the animal population is sufficient to obtain a return on investment. In that context, the EU is often viewed as a single region. PostBrexit, to ensure that access to new medicines is not delayed for British animals and to encourage companies to remain in or even move to the UK, some form of UK/EU ‘mutual recognition’ which permits a UK-registered product access to the ‘EU region’ animal population could be a solution. Tackling antibiotic resistance As resistant bacteria can readily move with the international movement of people, animals and food, consideration needs to be given to the question of how the UK can align with the EU in tackling this important global issue. Ensuring food safety and continued trade To ensure food is free from any harmful residues, maximum residue levels (MRLs) are set for withdrawal periods (i.e. the time between an animal receiving the last dose of a veterinary medicine and the first collection of foodstuffs, e.g. milk). The EU participates in Codex, a body responsible for setting international MRLs, which helps facilitate trade in food. The UK will need to review and increase its participation in Codex meetings in the future. Animal diseases do not respect borders Disease can be transferred both where there is trade in animals and animal products and in the absence of such trade. In the future, the UK will still need to continue to co-operate with its European neighbours to ensure that appropriate measures are in place to prevent and control disease outbreaks. Future regulation of veterinary medicines in the UK NOAH members, in particular those operating in a multinational environment, both in and outside the EU, need to retain access to the UK market. For example, a possible regulatory model may be a new UK/EU bilateral treaty with the UK recognising the EU veterinary medicines legislation and continuing technical input from the UK offering expertise and capacity to the EU. This would offer benefits to both parties given the prominent role that the UK regulator Volume 4 Issue 3


REGULATORY & MARKETPLACE has played in the EU regulatory network for veterinary medicines. A small number of animal health products are currently regulated by the European Food Safety Authority (EFSA). Post-Brexit, a UK process will need to be developed for them. In parallel, NOAH worked closely with VMD to help identify those issues that need to be addressed to allow the UK regulatory process to continue to function on Day Zero: effectively the first day after the two years following the Article 50 trigger. VMD will be working on these as part of its preparatory activities – without clear signs as to what Brexit will look like these need to be able to assume a ‘no deal’ scenario. The UK animal health sector is relatively small (circa £625m ex-factory sales per annum), but it has a big impact on many other sectors and is critical to their success. There is also much commonality on what is needed, for example with the human pharma sector (also currently heavily reliant on the EU regulatory process through the European Medicines Agency (EMA)), with the other associations in the agricultural technology, supply, knowledge transfer and innovation sphere and with the vet profession and farming organisations. Much has been done in collaboration – sharing requirements and ideas through formal alliances such as the Agri-Brexit coalition2, through collaboration with the life sciences group and regular discussions with, for example, the British Veterinary Association (BVA) and National Farmers’ Union (NFU). Working together enables NOAH to magnify its voice in the clamour of sectors vying for politicians’ attention in developing UK policy, but NOAH is also making sure that the specific needs of and opportunities for the animal medicines sector are recognised. Key to this is communication. To this end, NOAH is developing a series of reports, called the Brexit Barometer. The uncertainty about Brexit and how negotiations will develop are manifested in NOAH’s inaugural Brexit Barometer report3, which was developed following a NOAH Brexit workshop event in London in May 2017 where representatives from 16 NOAH member companies and other key stakeholders came together to discuss and debate the impact of the EU exit on the animal medicines sector. The findings revealed that while there were clear levels of optimism from the majority when it comes to animal health and welfare, 40% of attendees said they felt ‘somewhere in the middle’ when asked to declare whether they felt optimistic or pessimistic about the overall future of the industry. With 35% feeling optimistic and 25% feeling pessimistic, steering members and stakeholders towards optimism through a collaborative relationship with the Government becomes fundamental to the future success of the industry.

1. Animal health and welfare 2. Public health and food production 3. Post-licensing controls for the overall market Alongside tracking sentiment, the report sets out a series of specific opportunities for each of the six topic areas, outlining what the industry and its stakeholders require from government to realise each of these. NOAH will be working closely with its members and stakeholders to communicate and address this feedback in the coming months. It is good to see a degree of optimism among our diverse audiences. NOAH is very conscious of the need to translate the largest proportion (40%) of undecided respondents into positive sentiment to enable us to capitalise on Brexit despite the uncertain political climate. People are prepared to embrace Brexit, but providing the sector’s needs are recognised. What the UK Government needs to do has been recognised, for example by Neil Parish MP, Chair of the Environment, Food and Rural Affairs (EFRA) Select Committee.4 He said that Brexit will affect us all and the process will not be simple. The animal medicines industry plays a vital role in supporting the health and welfare of the animals that produce food from UK farms and the pets that share our homes. Government will need to work closely with the sector to address issues ranging from building on the UK’s existing high standards of animal welfare and protecting against a post-Brexit labour shortage, to ensuring that innovative medicines and vaccines can continue to be brought to the UK market through appropriate regulation and trading agreements between the UK and the EU. The results of this initial report very clearly illustrate that the future of the industry lies very much in the balance, and steering it towards optimism and success needs to be a priority in view of the challenges that lie ahead.

The report will be repeated to track shifting sentiment as the Brexit process unfolds. Attendees at the workshop examined the exit from the EU and its impact on the industry through six different lenses: animal health and welfare, public health and food production, trade and investment, R&D and innovation, bringing new products to market and post-licensing controls for the overall market. Brexit event attendees were also asked to share their levels of optimism on each of the six areas. In order of positivity, the top three topics were as follows: www.animalhealthmedia.com

Figure 1: NOAH Brexit Barometer 1 – optimism on different aspects of Brexit in relation to the animal health sector

The report says that after it leaves the UK, the UK can be a well-funded global centre for research and development and innovation supported by talent from around the world (Figure 1). International Animal Health Journal 11


REGULATORY & MARKETPLACE But the Barometer identified certain things that the UK Government needed to do to help enable this to happen: • Provide guidance on securing continued collaboration and funding for the future through EU framework programmes • Provide clarity over future funding for scientific research to avoid erosion of the UK veterinary science base • Explore opportunities to access new collaboration and funding, both nationally and globally • Explore opportunities to collaborate with other partners beyond the EU • Consider funding availability for UK-based scientists to ensure the UK retains its world-leading status in veterinary science research • Set out a clear single system for attracting talent from around the world • Define the role of the animal health and welfare industry and promote cross-industry collaboration • Reduce administrative burdens and improve the protection of companies’ intellectual property and technical documentation. In relation to bringing new products to market, the Barometer showed the sector at its least optimistic (Figure 1). The UK can provide the most streamlined and simplified route to market for product manufacturers – introducing an innovative licensing system, removing unnecessary administrative burden and working with industry to develop a regulatory model which encourages innovation. But to realise this opportunity there is a lot that needs to be done: • Promote the UK as a place to do business • Update UK regulations to reflect the benefits offered by the new European regulation of veterinary medicines, enabling us to achieve continued innovation and positioning within the market • Avoid regulatory divergence in technical data requirements for product registrations • Secure a seat for the UK at the VICH • Provide stability, certainty, openness and transparency throughout the exit process • Secure the status of EU nationals to retain expertise in the UK • Ensure that access to new medicines is not delayed for British animals • Ensure an environment that encourages companies to remain in or move to the UK • Develop a form of ‘mutual recognition’ which permits a UK-registered product access to the ‘EU region’ animal population • Safeguard regulatory efficiencies and retain access to current EU marketing authorisation systems as well as electronic submission portals and databases • Recognise that the VMD has the expertise and flexibility to manage the evaluation of innovation medicines. The UK will be able to control its imports and supply chain – drawing on the VMD as a resource for pharmaceutical inspection, providing improved education (for example about improvements to pain management, vaccination or better ways to manage antibiotic use) and managing the potential for counterfeit products (Figure 1). To realise this opportunity, we need government to: • Recognise the important role of the animal health industry during the exit process • Provide continuity with existing and future EU legislation • Provide assurance that the UK does not lose its position as a market of first choice • During the UK’s exit timeline, maintain its level of influence 12 International Animal Health Journal

around policy within the EU • Minimise costs and admin burden for post-licensing controls • Support multi-national members in retaining access to the UK market through a possible regulatory model which may be a new UK/EU bilateral treaty, with the UK recognising the EU veterinary medicines legislation, and continuing technical input from the UK offering expertise and capacity to the EU • Develop a new process for the small number of animal health products currently regulated by the European Food Safety Authority (EFSA) • Ensure the continued ability to import actives and medicines and ensure that additional tariffs on these do not affect prices. One thing is clear: the UK animal medicines industry does not want to miss the opportunity presented by new veterinary medicines legislation, as proposed by the European Commission, with the benefits of reduced administrative burden and stimulating investment and innovation in our sector. The current EU Veterinary Medicines Directive is translated into UK law by the Veterinary Medicines Regulation 2013 – but this is of course under review and will not be finalised in time for it to be swept into the European Union (Withdrawal) Bill (or ‘Repeal Bill’). Yet the UK will need to mirror the new EU regulations where possible – such as licensing procedures and product packaging – to avoid barriers to trade or additional cost of complying with a dual UK:EU regulatory system. The animal medicines sector is not alone in this: it is a strong argument from the human pharma sector, citing fears of what a nodeal scenario could bring6. A letter from UK Health Secretary Jeremy Hunt and Business Secretary Greg Clark indicated this message has got through – they are fully committed to continuing a close working relationship with the EMA post-Brexit7. The statement was made in the context of human medicine, but NOAH has responded with a letter also published in the Financial Times8 saying the association agrees access to medicines for human patients is vitally important, but explains that we must also ensure that our pets and farm animals have continued access to the best veterinary medicines to protect their health and welfare. It says animal medicines are equally subject to the stringent regulatory controls of their human counterparts, based on EU legislation, using the EMA. Animal medicines are integral to the health and welfare of animals on our farms and the pets sharing 12 million UK households, as well as nearly 10,000 assistance animals and 1500 working dogs. The Barometer report sets out a clear opportunity for the UK to be the benchmark for animal health and welfare on a global stage – through, for example, setting progressive, flexible and innovative legislation. This could include recent government suggestions for incentivising good health and welfare, with George Eustice, MP, Minister of State, Department for Environment, Food and Rural Affairs, stating that he wishes to place ‘animal welfare at the heart of the design of future agricultural policy’9. Prevention of disease is of course an important part of that. The Brexit Barometer’s publication coincided with warnings from the House of Lords (in its EU Select Committee’s Brexit: Farm Animal Welfare report10) that potential trade deals post-Brexit could threaten health Volume 4 Issue 3


REGULATORY & MARKETPLACE and welfare standards for farm animals, showing that government needs to take decisive action to safeguard the competitiveness of those farming to the UK’s high health and welfare standards as well as ensuring continued access to medicines for our vets, farmers and pet owners. While optimism remains high (Figure 1), the animal medicines industry needs a continuation of its high standards of health and welfare to help tackle antibiotic resistance and to put the UK in a strong influencing position with our ability to trade. Six key measures in relation to health and welfare that government needs to take to realise the opportunities were outlined in the report. These are: • Maintaining the current Animal Welfare Acts and evolving them to secure the UK’s position from ‘Day 0’ • Ensuring the industry is not disadvantaged by lack of veterinary medicines availability during the transition period and beyond, as new products come on the market • Ensuring that veterinary services are available in inner city and rural areas throughout the UK • Ensuring that a cross-border programme is in place to maintain cooperation between the UK and Europe • Recognising that animal diseases do not respect borders and co-operating with our European neighbours to ensure that appropriate measures are in place to prevent and control disease outbreaks • Balancing first-class welfare standards with creating a level playing-field for UK farmers and ensuring that British product does not become uncompetitive. This shows the sector sees a very clear opportunity for the UK to show leadership when it comes to animal health and welfare; industry is united in supporting high standards of animal welfare post-Brexit10. Good animal health is integral to good welfare, and we support the report’s acknowledgement that the veterinary profession is integral to the welfare role. Our sector provides tools such as vaccines to help the veterinary profession prevent disease and suffering, and medicines to treat where needed. In summary, NOAH is confident about the future of animal health after exit from the EU, but delivering on the sector’s priorities is a complex challenge. It requires all parts of industry to come together to help address the challenges and to collectively harness the opportunities, while speaking up to government about exactly what support is needed to ensure business continuity. REFERENCES 1. NOAH Brexit position paper https://www.noah.co.uk/ medicine-topics/brexit/ 2. Agri-Brexit Coalition http://www.agri-brexitcoalition. org.uk/ 3. NOAH 1st Brexit Barometer Report https://www.noah. co.uk/wp-content/uploads/2017/07/NOAH-BrexitBarometer-Summer-17-6pp-A4-vf.pdf 4. Neil Parish MP, Chair of the Environment, Food and Rural Affairs (EFRA) Select Committee, personal communication (NOAH Members’ Day, 14 June 2017) 5. The European Union (Withdrawal) Bill http://bit. ly/2sTov55 6. Drug firms fear bitter pill of a ‘no deal’ Brexit: Daily Telegraph, 17 June 2017 http://www.telegraph.co.uk/ business/2017/06/17/drug-firms-fear-bitter-pill-nodeal-brexit/ 7. The UK wants to continue to work with the EU on medicines: letters (Jeremy Hunt and Greg Clark), Financial Times, www.animalhealthmedia.com

4 July 2017 https://www.ft.com/content/a94326ac5dbd-11e7-9bc8-8055f264aa8b?mhq5j=e3 8. The health of our livestock and pets is important too: letters (Dawn Howard), Financial Times, 6 July 2017 https://www.ft.com/content/0b700eac-60e4-11e791a7-502f7ee26895?mhq5j=e3 9. Leaving the EU: Animal Welfare Standards in Farming, Hansard, column 93WH (George Eustice) 17 January 2017 https://hansard.parliament.uk/Commons/2017-01-24/ debates/7E2FCDD9-C80D-4488-92C5-1783E703AC45/ LeavingTheEUAnimalWelfareStandardsInFarming 10. House of Lords European Union Committee Report Brexit: Farm Animal Welfare, 5th report of session 2017-19, published 25 July 2017 – HL Paper 15 https:// publications.parliament.uk/pa/ld201719/ldselect/ ldeucom/15/1502.htm

Dawn Howard Chief Executive of NOAH. Prior to joining NOAH in 2014 Dawn was based in Brussels and spent a number of years representing UK agriculture in the office of the UK National Farmers Union where her responsibilities included animal health and welfare. She later headed up the European body for farm animal breeders, EFFAB. Dawn previously worked in Defra’s Animal Health and Welfare policy unit in Westminster and prior to that both Plant Health and pesticides policy in York, originally joining as a field-based inspector. Whilst originally qualified as a botanist, Dawn has a passion for raising animal health and welfare standards. Email: d.howard@noah.co.uk

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Veterinary Clinical Studies and Quality Assurance VICH GL9 GCP1 is the principle source of guidance for veterinary Good Clinical Practice (GCP)studies; it is from here we take our lead. Quality assurance (QA) in veterinary clinical studies is the responsibility of all study personnel, as defined in VICH GL9 GCP. In the guidance, however, the role of quality assurance staff in veterinary clinical studies is ill-defined. This article gives additional guidance on QA audit. VICH GCP guidance has been adopted by health authorities, including both the USA’s Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for veterinary clinical studies2,3. The references to quality assurance and quality audit in the VICH guidance include: Audit A systematic and independent examination of studyrelated activities and documentation to determine whether the study being evaluated is or was properly conducted, and whether the data are or were recorded, analysed and accurately reported according to the study protocol, studyrelated standard operating procedures (SOPs), GCP and the applicable regulatory requirements. Good Clinical Practice (GCP) A standard for the design, conduct, monitoring, recording, auditing, analysis, and reporting of clinical studies. Adherence to the standard provides assurance that the data and reported results are complete, correct and accurate, that the welfare of the study animals and the safety of the study personnel involved in the study are ensured, and that the environment and the human and animal food chains are protected. Pre-established systematic written procedures for the organisation, conduct, data collection, documentation and verification of clinical studies are necessary to assure the validity of data and to ensure the ethical, scientific, and technical quality of studies. Data collected from studies designed, conducted, monitored, recorded, audited, analysed and reported in accordance with this guidance can be expected to facilitate the review process, since the regulatory authorities can have confidence in the integrity

of studies which follow such pre-established written procedures. The assurance of quality of every aspect of the study is a fundamental component of sound scientific practices. The principles of GCP support the use of QA procedures for clinical studies. It is perceived that the sponsor would be the party responsible for the QA functions for these studies. All participants in clinical studies are encouraged to adopt and adhere to generally recognised sound QA practices. Quality Assurance (QA) A planned and systematic process established to ensure that a study is performed and the data are collected, documented (recorded) and reported in compliance with this guidance and the applicable regulatory requirements. Permit monitoring and quality auditing of a clinical study (requirement of the investigator). Ensure the quality and integrity of data from clinical studies by implementing quality audit procedures that are consistent with well-recognised and accepted principles of quality assurance (requirement of the sponsor). Audit certification by auditor, consisting of the dates of site visits, audits and when reports were provided to the sponsor. Study documentation should be audited by the sponsor’s quality audit procedures, consistent with well-recognised and accepted principles of quality assurance. When a quality audit is conducted, the auditor should prepare a report for the sponsor which details the auditing process and which certifies that the audit has been conducted. It is the sponsor’s responsibility, either person or institution, to ensure appropriate QA audit activities are undertaken for a clinical study according to pre-written approved SOPs. An audit is an activity independent of the management of the study, hence the role for QA personnel. Well-recognised and accepted principles of quality assurance audit will include protocol, investigator site and

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final study report audits. The numbers and scope of audits for GCP studies will be defined in the sponsor SOPs. Audit procedures will ensure a risk-based approach, focusing resource where most critically required. In a clinical study where electronic document capture (EDC) is used, QA may undertake audit of the study-specific EDC qualification, that is the user acceptance testing or performance qualification, before initiation of the study.

other organisations and assess standards to benchmark where available. The Research Quality Association, Animal Health Committee and the Society of Quality Assurance Animal Health Speciality Section provide useful information. These organisations have provided information, articles and papers on veterinary QA activities.6,7

Audit certification, a signed document by QA providing a listing of the audits undertaken and the dates of reporting by QA to the sponsor, is included in the final study report.

1. International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products Good Clinical Practices, Good Clinical Practices, VICH GL9 (GCP) June 2000 - Implemented in July 2001 2. http://www.ema.europa.eu/ema/index.jsp?curl=pages/ regulation/general/general_content_000072. jsp&mid=WC0b01ac05800268ad 3. https://www.fda.gov/downloads/AnimalVeterinary/ GuidanceComplianceEnforcement/GuidanceforIndustry/ UCM052417.pdf 4. http://www.ema.europa.eu/docs/en_GB/document_ library/Other/2014/12/WC500178525.pdf 5. https://www.gov.uk/government/uploads/system/ uploads/attachment_data/file/517483/GCP_ INSPECTIONS_METRICS_2014-2015__final_11-04-16_.pdf 6. https://www.therqa.com/good-practices/animal-health/ 7. https://www.sqa.org/sqa/About_SQA/Specialty_Section/ Specialty_Sections.aspx

In veterinary clinical studies, the study monitor has the overall responsibility to ensure the study is conducted according to VICH GCP, the study protocol and study procedures. The role of QA includes assuring the sponsor that the monitor is undertaking their role correctly and fully. Reference is provided here to the regulated inspection metrics for the EMA4 (a dated but useful summary) and the UK Medicines and Healthcare Regulatory Agency (MHRA)5 human clinical study inspection metrics. The only agency undertaking routine audit inspections of veterinary clinical studies is the FDA and inspection metrics are not provided. The findings in veterinary clinical studies will generally follow the observations in human clinical studies and reference is provided to give guidance. The critical categories of observation in human clinical studies include: • Lack of compliance to the study protocol • Deficiencies in study monitoring • Issues in the final study reporting, including lack of integrity with the collected study data • Data integrity, including deficiencies in data recording Conclusion From the regulatory perspective, VICH GCP is singularly unhelpful with regard to the detail of QA activities in veterinary clinical studies. A trained and experienced quality auditor can add value, through audit, focused on study compliance in areas of clinical importance. To determine the level of audit for your facility, look to the practices of www.animalhealthmedia.com

REFERENCES

Iain McPhee Ian entered QA in 1980 with GLP requirements for veterinary development safety studies, and has established GMP & GCP quality systems. He led the RQA publication on The Monitor’s Role in veterinary GCP and has worked in a number of veterinary pharmaceutical companies, holding compliance roles in GLP & GCP, GMP and computer systems. Email: mcpheia1@gmail.com

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Data Protection – An Industry Success Story for New Zealand Agriculture Until recently, New Zealand had one of the worst data protection regimes for animal medicines in the developed world. This all changed in November 2016, when our Parliament passed a major law change to extend data protection. The law change was a result of more than 15 years of advocacy by Agcarm, with the resulting outcome being a significant win for animal medicine and crop protection manufacturers. At first, the Government was not interested in extending data protection – reasoning that it would be anti-competitive to generic-based companies, and would lead to product price increases for farmers. The organisation which lobbies on behalf of its farmer members, Federated Farmers, also did not initially support a law change – believing that farmers would end up paying higher prices for essential animal health products. Over a number of years, Agcarm lobbied industry and government to extend data protection, using case studies and comparing international agricultural trading competitor data protection levels. Agriculture’s critical role to New Zealand’s economy, and the need to incentivise less hazardous products, and provide new and innovative products to replace those no longer in use, or where resistance is occurring, were other drivers. New Zealand growers and farmers were missing out on new technology due to the lack of protection on the data proving that a product works, is safe for people and the environment, and that residues in produce are within acceptable limits. Farmers of minor species, such as goats, and growers of minor crops were especially limited by the lack of data protection. In the goat industry, the most commonly used veterinary medicines are drenches. The lack of protection meant that many anthelmintics had to be used ‘off-label’ – meaning that they were not tested or registered for goats. Off-label use limits export trade as many overseas customers do not allow it. An increase in protection means products can be registered with a label claim and a maximum residue limit set for that species. Animal health companies shelved plans to develop new uses, or launch products to treat new species, because of a lack of data protection. One example of a product that was not introduced to New Zealand was estimated to have potential sales of less than NZ$1 million a year. Because it was a new use of an existing compound, there was no data protection and could be quickly copied, so the company chose not to introduce it. This is because the cost of assembling the data package to market might cost more than NZ$500,000. Manufacturers need to provide this information in order to get approval from New Zealand’s two regulators: the Ministry for Primary Industries and the Environmental Protection Authority. The data package supplied in support 16 International Animal Health Journal

of an application represents a significant investment – costing hundreds of thousands of dollars to assemble. Under the old regime, this data was either not protected from competitors, or was not protected for long enough to satisfy the return on such a significant investment. There was no protection for adding claims for minor crops to product labels. This saw industry grower groups having to fund a significant portion of the data generation themselves. The research and development needed to register label claims requires trials (for residues and efficacy) to be carried out in New Zealand. Many close trading partners such as Australia, the USA and Canada have access to government funds, as well as longer data protection periods. This put New Zealand farmers at a disadvantage. The upshot is that farmers and veterinarians miss out on new and better products. The New Zealand Government eventually realised that to double primary industry exports – as it had set out to do – it would need to encourage innovative solutions for the agricultural sector. The ambitious target of increasing these exports from NZ$32 billion in 2013 to over NZ$64 billion by 2025 required some innovative measures for our primary industries. Data protection was an obvious solution as it would increase the availability of new and innovative animal health products for the agricultural sector, thus providing healthier and higher yielding livestock. In late 2016, political parties eventually agreed to extend data protection to encourage businesses to register new and innovative products required by the New Zealand agricultural sector. There was only one exception – the Green Party – who maintained an entrenched view that longer protection would lead to the greater use of harmful chemicals on our farms. The party also claimed that it would not allow access to confidential information on animal medicine formulations. This was disregarded by the Government, who agreed that the law change would incentivise the registration of products with lower hazard classifications that are less harmful to our environment. The Minister responsible for leading the changes was the Honourable Jo Goodhew, Minister for Food Safety. Agcarm met with Hon. Goodhew (and other political leaders) on several occasions to explain the need for the extension of data protection and the benefits that it would bring to agriculture in New Zealand. Her comment on the passing of the bill was that it was very important for the primary industry’s productivity and international competitiveness that our farmers have access to effective agricultural compounds. The Government welcomed Agcarm members’ commitment to ensuring extended data protection, and she looked forward to seeing the positive impacts that it would have on our country. Allied industry groups also changed their view, as innovation became viewed as critical to the future growth in farming. A number of groups, such as the deer industry and Federated Farmers provided supportive submissions to the Primary Production Select Committee hearings on the new laws, which assisted in influencing decision-makers. Volume 4 Issue 3


REGULATORY & MARKETPLACE Summary of Changes

New Registrations

New Provisional Registrations

Variations to Registrations for one or more of the following situations: a) A purpose listed in the definition of an agricultural compound; b) Rate at which the product is applied; c) When the product must or must not be applied; d) How the product is applied; e) The withholding period for the product Reassessment of Registrations

Previous provisions

New provisions

Innovative Trade Name Products

Five years’ protection

10 years’ protection

Non-innovative Trade Name Products

No protection

Five years’ protection

Innovative Trade Name Products

Five years’ protection

Five years’ protection. Can be extended up to a further 10 years if it is subject to a new registration of the same innovative trade name product.

Non-innovative Trade Name Products

No protection

Five years’ protection. Can be extended up to a further five years if it is subject to a new registration of the same noninnovative trade name product.

Innovative Trade Name Products

No protection

Either the longer of the two periods of: a) End date for the protected period for the 10 years; or b) Five years from the granting or refusing the variation.

Non-innovative Trade Name Products

No protection

Five years

Trade Name Products

No protection

Five years’ protection

Note: An ‘Innovative Trade Name Product’ refers to a product containing an innovative active ingredient – meaning the active ingredient is not in any previous registered product. Data protection commences on granting or refusing of an application.

The Agricultural Compounds and Veterinary Medicines Amendment Act extends the period of protection for confidential information given in support of an application to register an innovative trade name product and also expands the scope of data protection coverage to include confidential information provided in support of applications to register noninnovative trade name products and uses. With the passing of the new law, it is anticipated that a number of more targeted, environmentally-friendly and fit-for-purpose products will be researched, tested and brought to New Zealand. For our farmers and growers, this means that the toolbox available for protecting crops and treating animals will increase and improve. It is hoped that our country will see a greater investment in research and development, which will increase productivity, sustainability and international competitiveness. It will also benefit trade and animal welfare. Now there is an incentive for product manufacturers to invest in researching solutions specifically for New Zealand pests and diseases. This means growers and grower groups can concentrate on what they do best, or invest in other causes such as preventing biosecurity incursions. www.animalhealthmedia.com

Access to new chemistry is also essential to replace older, less sustainable products. Newer active ingredients and formulation types tend to be ‘softer’ chemistry than those traditionally used and, as such, have lower hazard classifications which pose less risk to human health, nontarget organisms and the environment. One of the key endeavours outlined by the Government is facilitating new antimicrobials to enter the market with novel modes of action that may be effective against microbes. With the new data protection regime, manufacturers will be encouraged to register new products in New Zealand, thus providing the necessary incentives to see antimicrobials enter the animal health market. It also allows New Zealand farmers and growers access to new products favoured by trading partners. Access to the newest advances in technology allows them to comply with international best practice for the environment and food safety – and be internationally competitive. They are also more likely to have maximum residue levels set in our export markets. A greater variety of new products will mean more solutions for growers and more treatments for animals. It does not mean that product use will increase overall. Instead, there will be more to choose from – ones that in most cases will be more environmentally-friendly, more effective and more targeted. International Animal Health Journal 17


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Mark Ross, Mark Christie (DuPont New Zealand) and Paul Koffman (MSD Animal Health) ready to present to Parliament on data protection.

At this stage, it is too early to tell how much of an effect the extended data protection laws have had on the registrations of new and innovative animal medicines. However, it is anticipated that over time an increase in animal medicine registrations will occur in New Zealand, with a big driver being an additional five years to gain a return on the investment required to bring the medicines to the market. Data Protection vs Patents Amongst the New Zealand public, there is often confusion about the link between patents and data protection. Some assume that a new active ingredient brought into New Zealand is automatically covered by a 20-year patent. This is incorrect. Patent and data protection are two distinct intellectual property rights. Patent protection is the reward you receive for disclosing your invention (investment in innovation) by preventing another party from using that invention in any form, for a defined period of time, while data protection is the reward you receive for the cost and risk associated with generating data on the required health, efficacy, and environmental safety studies. During the lobbying for extended data protection, it was important to clarify this misunderstanding as it is easy to reach an incorrect view that a 20-year patent negated the need for data protection. A patent does not protect the data required for market approval, only the invention. Innovator companies must patent new active ingredients very early in their development. This ensures their invention and significant early investment is protected. However, it can take a further 10 years to fully develop and gain approval to sell a product based on the new active. This time delay significantly erodes the benefits of the 20-year patent term. Hence, the effective patent period is typically only 10 years. Markets for products develop over many years and at varying times around the world. It can take many years 18 International Animal Health Journal

before innovator companies see a market opportunity to bring a new active to New Zealand, which represents less than one per cent of the global market in agrichemicals and animal health products. Decisions about introducing an active ingredient to New Zealand are often made after a new active has come off patent, or at the end of the 20-year patent period. New Zealand’s prior minimal data protection was, therefore, a key influencer on the decision to introduce the active ingredient into our country. Doubling the data protection to 10 years for new actives encourages the registration of active ingredients new to New Zealand. This benefits New Zealand agriculture in three ways: 1. Bringing new technology to our farmers. 2. Increasing the pool of active ingredients that can be used to minimise the development of resistance to antibiotics and crop protection products. 3. Increasing the pool of products for subsequent approval/registration by generic companies (after the patent and 10-year data protection period has expired)

Mark Ross Chief executive of Agcarm since February 2015. He has over 25 years’ experience in the agricultural industry, most recently as General Manager of Policy and Advocacy with Federated Farmers of New Zealand. He has also held senior positions at the Ministry for Primary Industries. Mark has an Executive MBA from Massey University and postgraduate agricultural qualifications from Lincoln University. Email: mark.ross@agcarm.co.nz

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International Animal Health Journal 19


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What Feed Statistics Tell Us about the Health of Animal Production and the World Economy For the past seven years, Alltech has analysed the animal feed industry in depth, resulting in a oneof-a-kind annual survey that demonstrates the globalisation of what was once the most local of sectors: agriculture. In a global food chain, inputs such as animal feed reflect the overall health and evolution of both the industry and the economy at large. Changes in the demand for, and pricing of, animal feed reflect trends in consumer preferences, population growth, investment opportunities, economic development, animal husbandry and overall economic circumstances. Drawn on data from 130 countries, including visits to more than 30,000 feed mills, the annual Alltech Global Feed Survey (GFS) report has become a bellwether of global economic trends, sometimes flagging changes before other indicators do. The market for animal feed has a direct impact on food prices, making the relative health of the global feed industry an interesting proxy for the health of the agricultural sector and, by extension, the overall global economy. Although the US and China are the two biggest markets, there are plenty of interesting insights from around the world, including some interesting growth in the pet food industry. Eight Wonders from the 2017 Alltech Global Feed Survey 1. Barn to Bank Account: Feed Prices Directly Impact the Price of Food The cost of our food is directly affected by the cost of the food that our food eats: Approximately 70% of the cost of producing meat, milk and eggs is determined by the price of feed, which in turn is driven by the price of grains and vegetable proteins such as soybeans. This year, the GFS showed global drops in the cost of feed for pigs (5%), laying hens (7%) and chickens (7%) compared to the previous year. Although these price drops come at the expense of margins for crop farmers, they reduce the cost of raising animals. Unfortunately, lower feed costs don’t translate to immediate price cuts at the grocery store. First, the decreases vary significantly by region. More importantly, as with many price changes, it takes time before the benefits trickle down to the grocery store shelf. 2. Agricultural Businesses are Growing but Consolidating The feed industry is showing both rationalisation and consolidation. Over the last five years, while global feed production has grown steadily at 1.6% per annum, there has also been a drop in the number of feed mills (7% in the last year). Fewer mills producing more feed reflect the continued consolidation of the feed industry. The consolidation parallels the growing demand for animal protein, which is expected to increase 73% by 2050 as incomes rise. The growing market both encourages and facilitates farmers and feed millers to find more efficient ways to produce meat, milk and eggs. 20 International Animal Health Journal

3. Europe Reforms The European Union (EU) established the Common Agricultural Policy (CAP) in 1962. Designed to ensure food security for the continent, it was spectacularly successful, leading to excess production and what the press termed “mountains” of butter and “lakes” of wine and milk as farmers increased the productivity of their farms in response to attractive prices. As a reaction to this, the EU capped production through quotas, which led to further market distortions. A substantial reform in the last two years restructured CAP payments so that European farm prices are now linked to global prices. Quotas were eliminated, but the EU maintained a single payment subsidy to encourage farmers to remain on the land. 4. Heading South to India, which is Not “Heading South” At All! India is expected to soon pass China in total population, making it the most inhabited country on the planet. Its economy is projected to grow at 8%, thanks to the Goods and Services Tax, according to Forbes. This is strongly reflected in the country’s high dairy feed production, which indicates the populace’s love of milk, particularly as a source of protein for the roughly 40% of Indians who are vegetarian. India is second in dairy feed production to the US, up 14% over last year, and overall number six in feed production. India’s fish farming is exploding, egg consumption is growing and consumption of chicken is substantially up over the past five years, although it saw a slight decrease in 2017 due to external factors. India is clearly the shining light in farming’s future. 5. China: Every Year is the Year of the Pig China and the US account for more than one-third of global feed production, but there are notable disparities in their focal areas: China leads in feed for pigs, chickens and aquaculture, while the US leads in beef and dairy. China produces more than 25% of the world’s pig feed: 75.5 million metric tons (mmt), double the next-largest producer (the US). However, the Chinese market is changing dramatically as the government moves to address food safety, pollution and other environmental concerns. A disproportionate number of these problems have originated on smaller farms, many of which are being forced out of business. It is estimated that the number of sows in China has decreased by nearly 40% over the past three years. Still, pig feed and pork meat production statistics have been relatively unaffected. The remaining farms are larger and more efficient and have increased their productivity to pick up the slack. Other countries, particularly the US and Brazil, have increased exports to China to meet the demand for pork by Chinese consumers.

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International Animal Health Journal 21


REGULATORY & MARKETPLACE 6. Fish: Riding the Wave of Consumer Demand for Sustainable and Healthy Protein Last year, farmed fish production surpassed wild-caught fish for the first time. Aquaculture is the now the fastestgrowing sector in the feed business, up 12% in 2016. As the health benefits of omega-3 fatty acids (particularly DHA) have become known, the demand for fish has increased. Aquaculture will be an essential part of meeting prosumers’ demands for sustainable fish.

there is a developing interest in these markets and the value of this information is increasing. Pet food trends mimic those of the food business in general, and spending on pet food mirrors economic development and progress. The pet food industry is growing robustly, with a 22% increase over the last five years (4% per annum). Additionally, it should be noted that consumers are trading up to premium feeds, so the value of pet food is increasing even more than volume.

7. Chicken: Becoming the World’s Favourite Meat There are more than 50 billion chickens grown each year in the world. Easy to raise and indigenous to most cultures and cuisines, the chicken (or near relatives) was domesticated about 3000 years ago. Requiring fewer natural resources to produce than any other land species and with a short lifecycle, chicken production has grown rapidly. Large-scale farms now dominate the industry, accounting for more than 75% of production. Growth in chicken production has driven the total amount of feed required, which is not yet being offset by genetic improvements in chicken digestion. According to the USDA, the world broiler meat production was 89.5 million tons in 2016 and is set to increase to a record 90.4 million tons in 2017. Continued growth will make chicken the world’s favourite meat within the next five years, moving pork into second place.

The growth in the pet food industry is also indicative of overall growth in the pet industry as a whole, including toys, clothing and veterinary care. In fact, the companion animal market in Brazil is expected to have a compound annual growth rate of 5.9% and reach $6.9 billion by 2020. What has been shown in the pet food portion of the survey is a growth in the past two years of 4%. Other countries have nearly doubled in the past two years, including both France and the UK. This further indicates the incredible growth of the pet food industry for well-developed nations as middle-class segments continue to grow in wealth and pets are viewed more and more as family members.

8. Pampered Pets: Food Demand Reflects Prosperity Pet food production statistics are not generally released, but there are ways to estimate production numbers. Seven of the top 10 producers are based in the US, and the US produced an estimated 8.1 mmt of feed for the pet industry (collectively, the EU produced over 8 mmt). This is still by far the highest-ranking country in pet food production, but other countries are increasingly growing their pet food production numbers as well. For example, Brazil was second in production with an estimated 2.5 mmt. Other countries with high pet food production rates include France, the UK, Germany and Mexico.

These developments in the pet industry are facilitated by online markets and spending. Even as people continue to rely more heavily on online purchasing for clothes, food and other main household goods, the same is true for those searching for pet products.

It is also good to note that several countries that had not previously reported estimation in pet food production included numbers for 2016. This is indicative of a couple of different things: growth, for one. But it may also show there are better reporting procedures of feed mills and manufacturers regarding pet food. This would mean that

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REGULATORY & MARKETPLACE

Veterinarians who want to understand the world of food production and the global winds that are shaping farming would do well to become familiar with this feed survey. The numbers capture trends and the degree to which animal agriculture is consolidating and intensifying in a way that other data does not. The growth in Africa and Asia, the correlation between horse and pet food with a country’s economy, and the continued growth in the consumption of poultry and farmed fish all reflect the macro trends that will shape the future of the animal health profession. How the GFS is Created For seven years, we have been collecting and analysing data on the global feed industry, gathering information from more than 130 countries, visits to more than 30,000 feed mills worldwide and local contacts, including local and regional feed associations. The result is the most comprehensive data available on the feed sector, which is now used by organisations such as the Food and Agriculture Organization of the United Nations (FAO.org) and the International Feed Industry Federation (IFIF.org) in setting policy and recommendations. Acknowledgement This article was an adaptation of an original post by Aidan Connolly on LinkedIn: http://bit.ly/2oHRCce.

Aidan Connolly He has been with Alltech for more than 25 years, initially in Ireland and afterward in France, Brazil and the United States where he is currently based at Alltech’s corporate headquarters near Lexington, Kentucky, USA, as Alltech’s chief innovation officer and vice president of corporate accounts. Email: aconnolly@alltech.com

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International Animal Health Journal 23


RESEARCH AND DEVELOPMENT

Important Facts about Mycotoxins that Every Dairy Producer Should be Aware Of The goal of the dairy farming industry is to supply dairy processing enterprises with high-quality milk that can be converted into highly nutritious milk products for human consumption. Milk quality is determined by the composition of its nutrients (i.e., fat, protein, lactose, vitamins and minerals), and the level of contaminants or undesirable compounds (i.e., bacterial cells, other cells, and toxins such as aflatoxin M1). Therefore, every dairy farm aims to maximise the level of nutritious components and minimise the levels of contaminants in milk. Many factors on farms are known to influence milk quality. These include dairy cow breed, season, nutrition, management, hygiene, storage, and transport. It is well established that many nutritional factors can contribute to the presence of contaminants and undesired compounds in the milk. Mycotoxins are toxic metabolites produced by fungi (moulds) which grow on animal feeds, including pasture, forages, cereal grain, by-products and straw. Hundreds of mycotoxins have been identified and one mould species can produce many different types. Feeding mycotoxins contaminated rations (mainly with aflatoxin B1 [AFB1]) can lead to the appearance of mycotoxins (mainly aflatoxin M1 [AFM1]) in milk. Although AFM1 is the main mycotoxin that is transferred from feed to milk, other mycotoxins can be transferred at lower rates and may contribute to reducing the milk quality. Fumonisin B1, α-ochratoxin, T-2 toxin, deepoxy-DON (DOM), and α-zearalenol can be transferred into milk when highly contaminated rations are fed. In addition, feeding mycotoxin contaminated rations may reduce fat and protein content, and increase somatic cell counts and bacterial load in milk; all of which contribute to significantly reducing the milk quality. Negative Effects of Mycotoxins in Ruminants Chronic exposure: Quite often problems are due to low levels of mycotoxins and may be expressed as just minor increases in “common cow problems”, especially with freshly calved cows. Acute exposure: Consumption of high levels of mycotoxins may give rise to symptoms including abrupt drops in milk production and feed intake, abortions, lameness and, in the most severe cases, mortality.

intoxications and dramatic changes in milk production and animal health status at high levels can be identified much more easily. Unfortunately, the most common and most difficult problem to identify occur when rations contain low levels of the mycotoxins and the health effects are sub-clinical. The presence of mycotoxins in feed is often connected with an increase in the incidence of metabolic disorders such as ketosis, retained placentas, displaced abomasums, mastitis, metritis, lameness, elevated somatic cell counts (SCC) and, consequently, slightly decreased milk production. Sub-clinical mycotoxicoses reduces profitability by lowering milk production and increasing expenses from additional veterinary therapies. Mycotoxins can be the primary agents causing acute health or production problems in a dairy herd, but are more likely to be a contributing factor to chronic problems including a higher incidence of diseases, poor reproductive performance, or suboptimal milk production. Mycotoxins exert their effects through four primary mechanisms: intake reduction or feed refusal, reduced nutrient absorption and impaired metabolism, alterations in the endocrine and exocrine systems, and suppression of the immune system. Recognition of the impact of mycotoxins on animal production has been limited by the difficulty in diagnosis. Symptoms are often non-specific and can be the result of a progression of effects, making a diagnosis difficult or impossible because of the complex clinical results with a wide range of symptoms. What Do We Need to Know about Aflatoxins in Ruminants Aflatoxicosis is the disease caused by the consumption of high levels of aflatoxins. At low levels of intake, usually there are no visual symptoms of aflatoxicosis, and as such the problem is often unnoticed. However, high concentrations of aflatoxins, or prolonged exposure at low levels, cause visual symptoms in cattle, and especially in young calves. Beef and dairy cattle are more susceptible to aflatoxicosis than sheep and horses, whereas young animals of all species are more sensitive to the effects of aflatoxins than mature animals. On the other hand, pregnant and growing animals suffer from aflatoxicosis less than young animals, but more than mature animals kept at maintenance (for example, breeding males).

Diagnosis of Mycotoxin Issues Symptoms are often either sub-clinical or are non-specific and easily confused with other disorders. Poor response to veterinary therapy is frequently an indicator that mycotoxins are implicated in a condition. Feed can be tested for mycotoxins but the accuracy of sampling and the cost of routine testing limit its practicality at farm-level.

Feed refusal, reduced growth rate, and decreased feed efficiency are the predominant signs of chronic aflatoxin poisoning. In addition, weight loss, rough hair coat, and mild diarrhoea may be observed in affected animals. Anaemia, along with bruises and subcutaneous haemorrhages are also frequent symptoms of aflatoxicosis. This disease may also impair reproductive efficiency, including abnormal oestrous cycles (too short or too long) and increased abortions. Other symptoms include impaired immune system response, increased susceptibility to other diseases, and rectal prolapse.

Mycotoxin Threat to Ruminants? It is extremely difficult to identify when mycotoxins are causing poor health and performance. Some mycotoxins, such as zearalenone, predominantly affect reproduction and are relatively easy to identify. Mycotoxins that can cause acute

The diagnosis of aflatoxicosis is often difficult because of the variation in clinical signs, gross pathological conditions, and the presence of secondary infectious diseases due to the suppression of the immune system. In addition, under commercial conditions, more than one

24 International Animal Health Journal

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International Animal Health Journal 25


RESEARCH AND DEVELOPMENT mycotoxin may be present in any contaminated feed, and this makes definitive diagnosis of aflatoxicosis quite difficult. The effects of aflatoxin contamination as the disease progresses depend upon the severity of caused liver damage. Thus, once overt symptoms are noticed, the prognosis is usually poor. Treatment should be directed at the severely affected animals in the herd, and measures should be taken to prevent further poisoning. Unfortunately, most lactating cows positive for aflatoxins in milk will not exhibit strong visual symptoms, and as such, prevention is always the best way to tackle this problem. With most mycotoxins being carcinogenic to animals and humans, there is a wide legislation framework regarding their monitoring in the food supply chain. Aflatoxin B1 is the most carcinogenic natural compound known. Aflatoxin M1 is the natural metabolite of aflatoxin B1 and it has a high carry-over rate to animal products such as milk. Fresh milk is regularly checked for aflatoxin M1; concentrations of M1 above 0.05 μg/kg in the EU, or 0.5 μg/kg in the US, are considered undesirable and such milk cannot be used for products that go into the human food chain. Contaminated milk must be discarded, and apart from the cost of lost milk revenue, the dairy producer must also suffer the cost of properly disposing of the contaminated milk! The carryover rate of aflatoxins from contaminated feed into milk in dairy cows is considered to average 1–2%. However, in high-yielding cows, which consume significant amounts of concentrated feeds, the carry-over rate of aflatoxin M1 into milk can reach 6.2%. Legal limits / Advisory guidelines* Mycotoxin

EU

FDA

Aflatoxin B1

5 ppb

20 ppb

Deoxynivalenol

5 ppm*

5 ppm*

Fumonisins

50 ppm*

15 ppm*

Ochratoxin A

250 ppb*

ND

Zearalenone

500 ppb*

ND

EU = European Union, FDA – US Food and Drug Administration ND = not determined

Table 1: EU and FDA legal limits for aflatoxins and advisory guidelines on safe levels for other mycotoxins in finished feed for dairy cattle *Commission directive, 2003; Commission recommendation, 2006

Can Rumen Effectively Detoxify Mycotoxins? The rumen has long been considered relatively resistant to mycotoxins because rumen microflora was assumed to naturally detoxify mycotoxins. However, stressed dairy cows such as those that are sick and/or lactating may have an increased rumen passage rate or overwhelmed rumen microflora and therefore not able to denature all of the toxins in contaminated feed. The same is for calves which are more susceptible to mycotoxins, as their rumens are not completely developed. A major factor in the absorption of mycotoxins in ruminants is rumen fermentation. Table 2 provides a summary of the degree of rumen mycotoxin bio-conversion and transfer to milk.

Mycotoxin

Main product of rumen metabolism

Reduction of biological potency

Estimated carry-over rates to milk

Aflatoxin B1

Aflatoxicol

Minor

0–12,4 µg/L

Aflatoxin M1

Minor

2,0–6,2%

Fumonisin B1

Unchanged

Unchanged

0–0,05%

Ochratoxin A

α-Ochratoxin

Significant

ND

T-2 toxin

Various

Significant

0,05–2%

DON

De-epoxy DON (DOM-1)

Significant

DON: 0,0001–0,0002%

Zearalenone

α-Zearalenol

None

DOM: 0,0004–0,0024% 0,06–0,08%

ND = Not determined; DOM-1 = deoxynivalenol metabolite-1

Table 2 - Rumen bioconversion and transfer of mycotoxins from feed to milk (Adapted from Fink-Gremmels et al., 2008) 26 International Animal Health Journal

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RESEARCH AND DEVELOPMENT Ruminal degradation of mycotoxins helps to protect the cow against acute toxicity, but may contribute to chronic problems, associated with long-term consumption of low levels of mycotoxins. Ruminal degradation of mycotoxins may have helped mask mycotoxin effects in dairy cows which were recognised in recent years, as production stresses have increased and as the industry has paid more attention to management details. Mycotoxins Exert their Effects through Several Means: 1. 2. 3. 4. 5.

Reduced intake or feed refusal Reduced nutrient absorption and impaired metabolism Altered endocrine and exocrine systems Suppressed immune function Altered microbial growth

Recognition of the impact of mycotoxins on animal production has been limited by the difficulty of diagnosis. The progression and diversity of symptoms are confusing, making diagnosis difficult (Hesseltine, 1986; Schiefer, 1990). The difficulty of diagnosis is increased due to limited research, occurrence of multiple mycotoxins, non-uniform distribution, interactions with other factors, and problems of sampling and analysis. Because of the difficulty of diagnosis, the determination of a mycotoxin problem becomes a process of elimination and association. Certain basics can be helpful (Schiefer, 1990): 1. Mycotoxins should be considered as a possible primary factor resulting in production losses and increased incidence of disease. 2. Documented symptoms in ruminants or other species can be used as a general guide to symptoms observed in the field. 3. Systemic effects, as well as specific damage to target tissues, can be used as a guide to possible causes. 4. Post-mortem examinations may indicate no more than gut irritation, edema, or generalised tissue inflammation. 5. Because of the immune-suppressing effects of mycotoxins, increased incidence of disease or atypical diseases may be observed. 6. Responses to added dietary adsorbents or dilution of the contaminated feed may help in diagnosis. 7. Feed analyses should be performed, but accurate sampling is a major problem. Symptoms vary depending on the mycotoxins involved, and their interactions with other stress factors and animals may exhibit few or many of a variety of symptoms. The more stressed cows, such as fresh cows, are most affected; perhaps because their immune systems are already suppressed. Economically Most Important Mycotoxins and their Effects in Ruminants Deoxynivalenol (DON) • Dairy cattle consuming diets contaminated primarily with DON (2.5 ppm) have responded favourably (1.5 kg milk, P<.05) to the dietary inclusion of a mycotoxin binder, providing circumstantial evidence that DON may reduce milk production (Diaz et al., 2001). • Field reports help substantiate this association (Gotlieb, 1997). Results from a Canadian study using six firstlactation cows per treatment during mid lactation (average 19.5 kg milk) showed that cows consuming DON-contaminated diets (2.6 to 6.5 ppm) tended (P<0.16) to produce less milk (13% or 1.4 kg) than did cows consuming clean feed (Charmley et al., 1993). 28 International Animal Health Journal

• DON has been associated with altered rumen fermentation (Seeling et al., 2006) and reduced flow of utilisable protein to the duodenum (Danicke et al., 2005). Fusaric acid interacts with DON to cause the vomiting effects, which earlier were attributed to DON alone and resulted in use of the trivial name of vomitoxin for DON (Smith and MacDonald, 1991). Remark: It is believed that DON serves as a marker, indicating that feed was exposed to a situation conducive for mould growth and possible formation of several mycotoxins. T2–toxin • In dairy cattle, T2-toxin has been associated with gastroenteritis, intestinal haemorrhages (Petrie et al., 1977) and death (Hsu et al., 1972). • Dietary T2-toxin at 640 ppb for 20 days resulted in bloody faeces, enteritis, abomasal and ruminal ulcers, and death (Pier et al., 1980). • Weaver et al. (1980) showed that T2-toxin was associated with feed refusal and gastrointestinal lesions in a cow. • Kegl and Vanyi (1991) observed bloody diarrhoea, low feed consumption, decreased milk production, and absence of oestrous cycles in cows exposed to T2-toxin. • Serum immunoglobulins and complement proteins were lowered in calves receiving T2-toxin (Mann et al., 1983). Gentry et al. (1984) demonstrated a reduction in white blood cell and neutrophil counts in calves. • McLaughlin et al. (1977) demonstrated that the primary basis of T2-toxin reduced immunity is reduced protein synthesis. Zearalenone (ZEA) • In a study with heifers receiving 25 ppm of ZEA, conception rate was depressed about 25% (Weaver et al., 1986). • Several case reports have related ZEA to oestrogenic responses in ruminants including abortions (Khamis et al., 1986). Symptoms have included vaginitis, vaginal secretions, poor reproductive performance, and mammary gland enlargement of virgin heifers. • In a study (Coppock et al., 1990), diets with about 660 ppb ZEA and 440 ppb DON resulted in poor consumption, depressed milk production, diarrhoea, increased reproductive tract infections, and total reproductive failure. • Towers et al. (1995) have measured blood ZEA and metabolites ("zearalenone") to estimate ZEA intake. Dairy herds with low fertility had higher levels of blood "zearalenone". Individual cows within herds examined by palpation and determined to be cycling had lower blood "zearalenone" levels than did cows that were not cycling. In this study, reproductive problems in dairy cattle were associated with dietary ZEA concentrations of about 400 ppb. Fumonisins • Osweiler et al. (1993) fed 18 young steers 148 ppm of fumonisin in 31 days. There were mild liver lesions found in two of six calves, and the group had lymphocyte blastogenesis and elevated enzymes indicative of liver damage. • Dairy cattle (Holsteins and Jerseys) fed diets containing 100 ppm fumonisin for approximately seven days prior to freshening and for 70 days thereafter demonstrated lower milk production (6kg cow/day), explained primarily by reduced feed consumption (Diaz et al., 2000). • Fumonisin carry-over from feed to milk is thought to be negligible (Scott et al., 1994).

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RESEARCH AND DEVELOPMENT α-Ochratoxin (OTA)

• In cattle, OTA is rapidly degraded in the rumen (to α-Ochratoxin) and thus thought to be of little consequence unless consumed by young pre-ruminant calves (Sreemannarayana et al., 1988). • With high-grain diets, less of the dietary ochratoxin may be degraded in the rumen and thus be more toxic in those situations (Hohler et al., 1999). • Mouldy alfalfa hay containing Aspergillus ochraceus was implicated as producing OTA associated with abortions in cattle (Still et al., 1971). • OTA in mouldy forage has also been implicated in cattle deaths (Vough and Glick, 1993). Ergot Alkaloids • Ergotism primarily causes a gangrenous or nervous condition in animals. Symptoms are directly related to dietary concentrations and include reduced weight gains, lameness, lower milk production, agalactia and immune suppression (Robbins et al., 1986). • Fescue infected with Neotyphodium sp. or Epichloe sp. may contain toxic alkaloids associated with “fescue toxicity” (CAST, 2003). Symptoms include lower weight gains, rough hair coat, increased body temperature, agalactia, reduced conception, and gangrenous necrosis of the extremities such as the feet, tail and ears. Aflatoxins • Symptoms of acute aflatoxicosis in mammals include: inappetance, lethargy, ataxia, rough hair coat, and pale, enlarged fatty livers. Symptoms of chronic aflatoxin exposure include reduced feed efficiency and milk production, jaundice, and decreased appetite. Aflatoxin lowers resistance to diseases and interferes with vaccine-induced immunity (Diekman and Green, 1992). • In beef cattle, Garrett et al. (1968) showed an effect on weight gain and intake with diets containing 700 ppb aflatoxin, but if increases in liver weights are used as the criteria for toxicity, 100 ppb would be considered toxic to beef cattle. • Production and health of dairy herds may be affected at dietary aflatoxin levels above 100 ppb, which is considerably higher than the amount that produces illegal milk residues (Patterson and Anderson 1982). • Guthrie (1979) showed when lactating dairy cattle in a field situation were consuming 120 ppb aflatoxin, reproductive efficiency declined, and when cows were changed to an aflatoxin free diet, milk production increased over 25%. • Applebaum et al. (1982) showed milk production was reduced in cows consuming impure aflatoxin produced by culture, but production was not significantly affected by equal amounts of pure aflatoxin. Economic Evaluation of Mycotoxin Deactivators in Dairy Cows Production losses due to mycotoxin contamination are clearly subject to a great number of factors and uncertainties. The losses are hugely variable in time and difficult to estimate. However, the effects of the contamination are often significant and can be long-lasting. The economic impact of mycotoxins is difficult to estimate even after an outbreak of mycotoxicosis. The most important losses are probably those associated with long-term underperformance. Estimates of this can be made on the basis of the information provided above. Thus, a simple simulation model was developed that allows for the estimation of production and financial losses due to the long-term subclinical impact of mycotoxins in dairy cattle.

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The following assumptions were made: • No change in dry matter intake or loss in milk production volume. • A decrease of 0.4% - point in milk fat and 0.1% - point in milk protein. • No penalising change in SCC, thus assuming almost ideal sanitary conditions of cows. • An increase in calving interval of 60 days and an increase in inseminations by 10% along with an increase in veterinary cost of 10%. • Application of an efficient mycotoxin deactivator restores losses by 80%. Under these assumptions, the model predicts that on a herd basis, mycotoxin contamination will cause losses in milk income of approximately 12% and that the addition of an efficient mycotoxin deactivator will restore losses to just 3% under the income level achieved in the absence of mycotoxins. Total farm revenue changed with similar percentages but variable costs or the operation costs increased by 3% in the presence of mycotoxins. The annual return over variable costs decreased from 14.5 to 7.6% due to the presence of mycotoxins. The cost of the mycotoxin deactivator for a continuous treatment throughout lactation and dry period was estimated at $ 28/cow. The application of this mycotoxin treatment led to an improvement in returns over variable cost to 12.3% due to an improvement in revenue of $ 225/cow. Consequently the return on investment (ROI) of the use of a mycotoxin treatment is approximately 7:1. The assumptions associated with these simulations are considered to be rather close to the current US operational conditions. The model can be adapted to other economic situations — for instance those applicable to the EU, Middle East or Latin America. However, following a number of simulations, it appears that the economic returns of mycotoxin deactivators under conditions where contamination is suspected will easily be equal or superior to the rather conservative estimates obtained with these analyses (Van Eys et al., 2016). REFERENCES 1.

2.

3.

4.

5.

6.

Applebaum, R.S., Brackett, R.E., Wiseman, D.W. and Marth, E.L. 1982. Responses of dairy cows to dietary aflatoxin: feed intake and yield, toxin content, and quality of milk of cows treated with pure and impure aflatoxin. J. Dairy Sci. 65:15031508. CAST, Council for Agricultural Science and Technology. 2003. "Mycotoxins: Risks in Plant Animal and Human Systems". Task Force Report No. 139. Ames, Iowa. Charmley, E., Trenholm, H.L., Thompson, B.K., Vudathala, D., Nicholson, J.W.G., Prelusky, D.B. and Charmley, L.L. 1993. Influence of level of deoxynivalenol in the diet of dairy cows on feed intake, milk production and its composition. J. Dairy Sci. 6:35803587. Commission directive (EU) No. 2003/100/EC of 31 October 2003. Amending Annex I to Directive 2002/32/EC of the European Parliament and of the Council on undesirable substances in animal feed, Official Journal of the European Union, 2003. Commission recommendation (EU) No. 2006/576/EC of 17 August 2006 on the presence of deoxynivalenol, zearalenone, ochratoxin A, T-2 and HT-2 and fumonisins in products intended for animal feeding, Official Journal of the European Union, 2006. Coppock, R.W., Mostrom, M.S., Sparling, C.G., Jacobsen, B. International Animal Health Journal 29


RESEARCH AND DEVELOPMENT and Ross, S.C. 1990. Apparent zearalenone intoxication in a dairy herd from feeding spoiled acidtreated corn. Vet. Hum. Toxicol. 32:246248. 7. Danicke, S., Matthaus, K., Lebzien, P., Valenta, H., Stemme, K., Ueberschar, K.–H., RazzaziFazeli, E., Bohm, J. and Flachowsky, G. 2005. Effects of Fusarium toxin contaminated wheat grain on nutrient turnover, microbial protein synthesis and metabolism of deoxynivalenol and zearalenone in the rumen of dairy cows. J. An. Physiol. and An. Nutr. 89:303315. 8. Diaz, D.E., Hopkins, B.A., Leonard, L.M., Hagler, W.M. Jr., and Whitlow, L.W. 2000. Effect of fumonisin on lactating dairy cattle. J. Dairy Sci. 83(abstr.):1171. 9. Diaz, D.E., Hagler, W.M. Jr., Hopkins, B.A., Patton, R.A., Brownie, C. and Whitlow, L.W. 2001. The effect of inclusion of a clay type sequestering agent on milk production of dairy cattle consuming mycotoxins contaminated feeds. J. Dairy Sci. 84 (abstr.):1554. 10. Diekman, D.A. and Green, M.L. 1992. Mycotoxins and reproduction in domestic livestock. J. Anim. Sci. 70:16151627. 11. Fink-Gremmels, J. Mycotoxins in cattle feeds and carry-over to dairy milk: A review, Food Add Contam. 25 (2008) 172-180. 12. Gentry, P.A., Ross, M.L. and Chan, P.K.C. 1984. Effect of T2 toxin on bovine hematological and serum enzyme parameters. Vet. Hum. Toxicol. 26:2424. 13. Gotlieb, A. 1997. Causes of mycotoxins in silages. pp. 213221. In: Silage: Field to Feedbunk, NRAES99, Northeast Regional Agricultural Engineering Service, Ithaca, NY. 14. Guthrie, L.D. 1979. Effects of Aflatoxin in corn on production and reproduction in dairy cattle. J. Dairy Sci. 62 (abstr.):134. 15. Hesseltine, C.W. 1986. Resumé and future needs in the diagnosis of mycotoxins. pp. 381385. In: J.L. Richard and J.R. Thurston, (Eds.) "Diagnosis of Mycotoxicoses". Martinus Nijhoff Publishers, Dordrecht, The Netherlands. 16. Hohler, D., Sudekum, K.H., Wolffram, S., Frolich, A.A. and Marquardt, R.R. 1999. J. Animal Sci. 77: 12171223. 17. Hsu, I.C., Smalley, C.B., Strong, F.M. and Ribelin, W.E. 1972. Identification of T2 toxin in moldy corn associated with a lethal toxicosis in dairy cattle. Appl. Microbiol. 24:684690. 18. Kegl, T. and Vanyi, A. 1991. T2 fusariotoxicosis in a cattle stock. Magyar Allatorvosok Lapja 46:467471. 19. Khamis, Y., Hammad, H.A. and Hemeida, N.A. 1986. Mycotoxicosis with oestrogenic effect in cattle. Zuchthyg. 21:233236. 20. Mann, D.D., Buening, G.M., Hook, B. and Osweiler, G.D. 1983. Effects of T2 mycotoxin on bovine serum proteins. J. Am. Vet. Med. Assoc. 44:17571759. 21. McLaughlin, C.S., Vaughan, M.H., Campbell, I.M., Wei, C.M., Stafford, M.E. and Hansen, B.S. 1977. Inhibition of protein synthesis by trichothecenes. p. 261–284. In J. V. Rodricks, C.W. Hesseltine, and M.A. Mehlman (ed.), Mycotoxins in human and animal health. Pathotox Publications, Park Forest South, Ill. 22. Osweiler, G.D., Kehrli, M.E., Stabel, J.R., Thurston, J.R. Ross, P.F. and Wilson, T.M. 1993. Effects of fumonisin contaminated corn screenings on growth and health of feeder calves. J. Anim. Sci. 71:459466. 23. Patterson, D.S.P. and Anderson, P.H. 1982. Recent aflatoxin feeding experiments in cattle. Vet. Rec. 110:6061. 24. Petrie, L., Robb, J. and Stewart, A.F. 1977. The identification of T2 toxin and its association with a hemorrhagic syndrome in cattle. Vet. Rec. 101:326326. 25. Pier A.C., Richard, J.L. and Cysewski, S.J. 1980. The implication of mycotoxins in animal disease. J. Am. Vet. Med. Assoc. 176:719722. 26. Robbins, J.E., Porter, J.K. and Bacon, C.W. 1986. Occurrence and clinical manifestations of ergot and fescue toxicoses. 30 International Animal Health Journal

Pp. 61–74. In: J. L. Richard and J. L. Thurston (Eds). "Diagnosis of Mycotoxicoses". Martinus Nijhoff Publishers, Dordrecht, The Netherlands. 27. Schiefer, H.B. 1990. Mycotoxicosis of domestic animals and their diagnosis. Can. J. Physiol. Pharmacol. 68:987990. 28. Scott, P.M., Delgado, T., Prelusky, D.B., Trenholm, H.L. and Miller, J.D. 1994. Determination of fumonisin in milk. J. Environ. Sci. Health. B29:989998. 29. Seeling, K., Lebzien, P., Danicke, S., Spilke, J., Sudekum, K.H. and Flachowsky, G. 2006. Effects of level of feed intake and Fusarium toxin contaminated wheat on rumen fermentation as well as on blood and milk parameters in cows. J. An. Physiol. and An. Nutr. 90:103115. 30. Smith, T.K. and MacDonald, E.J. 1991. Effect of fusaric acid on brain regional neurochemistry and vomiting behavior in swine. J. Anim. Sci. 69:20442049. 31. Sreemannarayana, O., Frohlich, A.A., Vitti, T.G., Marquart, R.R. and Abramson, D. 1988. Studies of the tolerance and disposition of ochratoxin A in young calves. J. Animal Sci. 66:17031711. 32. Still, P., Macklin, A.W., Ribelin, W.E. and Smalley, E.B. 1971. Relationship of ochratoxin A to foetal death in laboratory and domestic animals. Nature 234:563564. 33. Their Role and Economic Evaluation: Review. Modern Agricultural Science and Technology, ISSN 2375-9402, USA June 2016, Volume 2, No. 1, pp. 1-13. Doi: 10.15341/mast(23759402)/01.02.2016/001. 34. Towers, N.R., Sprosen, J.M. and Webber, W. 1995. Zearalenone metabolites in cycling and noncycling cows. pp.4647. In: Toxinology and Food Safety. Toxinology and Food Safety Research Group, Ruakura Research Centre, Hamilton, New Zealand. 35. Van Eys, J., Beloglazova, N. and Borutova, R. Mycotoxins in Dairy Cattle and Mycotoxin Deactivators. 36. Vough, L.R. and Glick, I. 1993. Round bale silage. pp. 117123. In: "Silage Production from Seed to Animal". NARES67, Northeast Regional Agricultural Engineering Service, Ithaca, NY. 37. Weaver, G.A., Kurtz, H.J., Mirocha, C.J., Bates, F.Y., Behrens, J.C., Robison, T.S. and Swanson, S.P. 1980. The failure of T2 mycotoxin to produce hemorrhaging in dairy cattle. Can. Vet. J. 21:210213. 38. Weaver, G.A., Kurtz, H.J., Behrens, J.C., Robison, T.S., Seguin, B.E., Bates, F.Y. and Mirocha, C.J. 1986. Effect of zearalenone on the fertility of virgin dairy heifers. Am. J. Vet. Res. 47:13951397.

Radka Borutova Business Development Manager, Nutriad International, Belgium. Radka Borutova graduated from University of Veterinary Medicine in Kosice, Slovakia and was awarded Doctor’s degree in Veterinary Medicine ( DVM) in 2005. For 5 years she worked at the Institute of Animal Physiology, Slovak Academy of Sciences, Slovakia followed by the Ministry of Agriculture of the Slovak Republic as Chief state counsellor. After 4 years at Biomin Holding GmbH as Product manager for MycofixR product line, she joined NutriAd International NV as Business Development Manager Mycotoxins. Email: r.borutova@nutriad.com

Volume 4 Issue 3


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RESEARCH AND DEVELOPMENT

Epidemiology and its Application to Animal Health Health research is diverse and varied and covers a spectrum from basic research – which describes the early discovery and development phase – to applied research. Each phase of research is essential to move scientific discovery forward and advance health. The production of new therapeutic compounds, for example, begins at the laboratory bench (basic) and proceeds through rigorous testing in clinical settings (applied) before they can be widely used in regular practice. Basic or ‘bench’ research usually focuses on identifying mechanisms of disease, understanding physiologic pathways, and developing new technologies, compounds, and therapeutics. Applied research provides the link between bench research and clinical application. It is through close cross-talk between the worlds of bench and applied research that researchers are able to innovate. The purpose of this editorial is to discuss details about the types of studies that fall under the umbrella of applied research, including their advantages and limitations, and their utility in advancing animal health. Interventional Research Applied research studies fall into one of two categories: interventional and observational studies. Each type serves distinct and important purposes. Interventional applied research consists of clinical trials. At their simplest, clinical trials (also known as randomised controlled studies) compare subjects in two groups: those who receive an intervention (a new drug or therapy) and those who do not (the control group). The groups are randomly chosen from the study population for placement into the different treatment arms. Subjects in a clinical trial for a new therapy receive either the therapy (for example a new compound or procedure or a novel combination of therapies) or the current standard of care, which may be placebo or an existing treatment. Clinical trials also can be used to measure a lifestyle or dietary intervention. The process of bringing new drugs and products to market requires clinical trials to establish drug safety and efficacy prior to licensing. The process of randomisation serves to prevent factors other than the intervention, such as age or gender, from affecting the outcome of the intervention. When randomisation works correctly, confounding is implicitly controlled, both for the factors that we can measure and those that we cannot (unmeasured confounding). For effective randomisation, three conditions must be met: a) investigators must not pre-determine treatment allocation for a study subject prior to enrolment; b) treatment allocation cannot be changed after a study subject is enrolled (with a few exceptions); and c) the subjects and their doctors must be kept naïve to the treatment allocation (known as masking) to prevent biased results.1 For obvious ethical reasons, we aren’t able to randomise study subjects to potentially deleterious exposures. 32 International Animal Health Journal

An alternative to traditional randomised controlled design in clinical trials is a cross-over design. In this type of study, a subject is allocated to all treatment arms at different periods of time with a wash-out period between treatment arms. This approach is useful because each study subject serves as his own control, thus confounding is minimal. Cross-over designs are only practical when the effects of the intervention are reversible, and are typically used to test drugs that have a short half-life. Study subject recruitment for clinical trials is tightly controlled: inclusion and exclusion criteria are often very narrow, and the results may not be applicable to all populations. For example, when testing a new therapeutic to treat canine diabetes, comorbidities (other diseases within the subject) are often an exclusion criterion. However, in practice, diabetic dogs frequently have multiple other conditions, potentially limiting the utility of results obtained from a study from which these dogs would have been excluded. Clinical trials usually are not designed to include enough study subjects to identify rare adverse events, nor do they typically last long enough to identify longterm outcomes associated with the intervention. An advantage of performing clinical trials in animals is that health outcomes tend to be achieved on an abbreviated timescale relative to humans; therefore, clinical trials on animals with spontaneous disease can serve to inform the intent and design of human trials, as well as advance veterinary medicine. Observational Research Observational studies are those that do not involve intervention and they can be descriptive or analytic. Researchers enroll study subjects and observe the study population to identify correlations between exposures and outcomes. In general, the advantages of observational studies include data collection on study subjects in the “real world” (i.e., the study conditions are not tightly controlled and subjects are simply observed as they go about their normal routines). Most observational research is aimed at etiology, or identifying potential causal associations for disease. Disadvantages of observational studies include a potential for unmeasured confounding (confounding that we cannot control for using statistical methods). There are many different types of observational studies. For the purposes of this editorial, we will focus on the most common types and their applications in animal health. Descriptive studies Descriptive studies have multiple purposes, including: monitoring and reporting on health status in populations, identification of emerging health problems, surveillance for health threats, establishing health priorities for a population, and helping generate hypotheses about the determinants of disease. These studies are not designed to test hypotheses but are an essential tool both for researchers to generate hypotheses and public health experts to allocate resources and identify areas of need. For example, researchers in Chile used documented occurrences of rabies in bats to make predictive maps of where the prevalence of rabies in the Volume 4 Issue 3


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RESEARCH AND DEVELOPMENT wild bat population is likely to be high.2 These results might be used to focus efforts to vaccinate domestic species in areas where the prevalence of rabies is predicted to be high. Ecologic studies In ecologic studies, researchers observe exposures and health outcomes in populations in order to identify correlations from these observations. The distinguishing feature of ecologic study is that it uses aggregate data; no individual-level data are included. Ecologic studies should not be confused with studies of ecology. Ecologic studies can be completed quickly and inexpensively. They are useful as hypothesis-generating research, to identify questions for more definitive studies, and often identify emerging diseases faster than other study designs. Because animals can often be sentinels for environmental toxins or emerging infectious diseases, they can be useful to identify health concerns for animals and humans alike. Because researchers are not measuring outcome or exposures in individual animals, ecologic studies cannot be used to determine whether the exposure and disease occurred in the same subject. In addition, it is difficult to establish temporality of exposure and disease in this study type. In animal health, an example of an ecologic study design was published by Rohr et al. In this study, one of the factors they studied was extinction events among a genus of amphibians and their distance from a pathogenic and invasive fungus. Authors found a positive correlation between extinction events and distance from areas where the fungus of interest exists.3 What the researchers were unable to say was that the extinct species were exposed to this fungus. This study demonstrates that the ecologic study design is important to establish potentially important associations; it cannot definitively say that fungal infection and mortality occurred in the same individual. Case-series Case-series studies are used to describe characteristics among a group of study subjects who have an outcome of interest (such as a disease). These studies can be useful to inform more definitive research but because only diseased subjects comprise the study population, no conclusions may be drawn about potential associations between exposures and disease. The scientific literature has many examples of case-series. A recently published case-series described the presence of selenium deficiency in eight foals with white muscle disease and went on to show that each of these foals come from areas in the Netherlands with selenium-deficient soil. Authors conclude from this study that selenium supplementation in selenium-deficient areas is indicated to prevent white muscle disease.4 This conclusion may be supported by additional research on this topic, though this study alone does not support that conclusion; from their data we do not know selenium levels in foals who are not affected by white muscle disease. Readers and researchers alike must take care not to draw conclusions that the data from this type of study cannot support. An exception is a study design called the self-controlled case series. This study design employs study subjects who have both the exposure and outcome of interest, and the study subject serves as his own control. It is typically used in pharmacoepidemiology to identify rare or long34 International Animal Health Journal

term adverse events associated with a drug or biological. Because it is necessary to establish that the exposure preceded disease, the self-controlled case series requires access to the subjectsâ&#x20AC;&#x2122; prior medical records. Researchers use this type of study when it isnâ&#x20AC;&#x2122;t feasible to compare subjects who got a drug to those who did not because those two populations are systematically different in ways that may bias results. Case-control studies In case-control studies, the study population is identified based on the outcome of interest. Cases (subjects with the outcome of interest) and controls (study subjects without the outcome of interest) are identified for inclusion in the study. Two types of case recruitment approaches may be taken: researchers can recruit cases that are prevalent (with existing disease) or incident (as they develop disease). It is generally preferable to recruit incident cases but that is not always feasible, particularly when a disease is especially rare. Researchers then gather data about exposures of interest, through a variety of methods including review of medical records, physiologic testing, or interview of study subjects or caregivers. Case-control studies are useful to study novel associations between exposure and disease because they are relatively inexpensive and expedient to carry out. They are also useful for studying rare diseases since the population is selected based on disease status. However, case-control studies have potential for bias because subjects (or their caregivers) may not correctly remember the chronology of exposure or clinical presentation of the disease, and they may remember exposures differentially based on disease status. If researchers are identifying exposures of interest in diseased patients at the time of study enrolment, it is impossible to say that exposure preceded disease, which is necessary to establish causal associations. Another limitation to the case-control study is that researchers canâ&#x20AC;&#x2122;t estimate absolute risk for an outcome in a population. An important concern in case-control studies is that cases and controls may differ in exposures other than the exposure of interest; it would be impossible to determine which of these exposures is associated with disease. Casecontrol matching is an attempt to address this problem by selecting cases and controls who share commonalities in pre-determined characteristics. For example, if age is an important risk factor for the development of an outcome (and not an exposure of interest), researchers will recruit cases and controls who are the same age. Matching, provided matched factors are not studied as a potential exposure, is an effective way to improve statistical efficiency in case-control studies. Because of their relative ease of execution, the scientific literature contains countless examples of case-control studies. In these studies, however, attributing causality can be complicated. For example, a recently published study compared vitamin D levels in dogs with osteosarcoma to age- and weight-matched controls. The authors found no difference in serum vitamin D levels between the cases and controls; they concluded that vitamin D insufficiency is not likely to play a role in the pathogenesis of canine osteosarcoma.5 However, if they had found lower vitamin D in osteosarcoma cases, it would not have been valid to conclude that that vitamin D insufficiency did play a role in the pathogenesis of canine osteosarcoma because of the potential for reverse causality. In other words, the research could not determine whether the deficiency caused the Volume 4 Issue 3


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RESEARCH AND DEVELOPMENT disease, or vice versa, without determining the chronology of the exposure and outcome conditions. Moreover, their conclusion that vitamin D insufficiency does not play a role in disease pathogenesis does not take into account the possibility that dogs who developed disease may have had low vitamin D at a time prior to diagnosis. This possibility is especially important in chronic disease epidemiology since the disease process is often protracted. Longitudinal studies Longitudinal studies are also known as cohort studies. In this type of study, a population (cohort) is identified based on a characteristic or characteristics they have in common and then they are followed to watch for the incidence for pre-defined health outcomes. In this type of research, subjects are free from the outcomes of interest at the time of enrolment. Although they are usually undertaken to study specific outcomes, cohort studies are robust enough to investigate many different outcomes; as long as study subjects do not have evidence of a given disease at enrolment, it is possible to study risk factors for that outcome in the study population. In addition, researchers can use cohort studies to define absolute risk in a population, and establish temporality of exposure and subsequent disease. The latter is important when trying to establish causal associations and this attribute makes cohort studies particularly useful for identifying disease etiologies. Cohort studies tend to take a long time to complete, making them ill-suited to studying urgent health issues. They also are expensive to execute and are usually designed and undertaken to build on the findings of less expensive study designs. Dogs make good cohort study subjects because we can feasibly study their entire lifecourse, something that we can’t do with humans. Cohort studies using animals as study subjects may provide a model for disease in people and inform research needs in humans. The Golden Retriever Lifetime Study is an example of a cohort study in animal health; researchers recruited a large number of privately-owned golden retrievers in the United States and are following them throughout their life-course to identify the incidence of and risk factors for four types of cancer that are common in this breed of dog.6 Retrospective studies In this type of study, researchers reach back in time using health records, vital records, or information collected by study subjects or their caregivers to gather data about potential past exposures of interest. The important distinction of retrospective studies is that the people providing the information were naïve to disease status at the time of collection. With the advent of computerised health records, retrospective studies have become more feasible and popular. These studies are advantageous because the data are collected in real time and therefore similar conclusions as cohort studies may be inferred. In addition, they are less expensive and faster to perform than traditional cohort studies. However, because they often use clinical records, which are not collected for the purpose of research, researchers cannot control the way in which the data were collected, which can complicate making inferences about findings. The Future of Observational Studies in Animal Health The human animal interface has undergone a sea change in the last 50 years. While we are generally much further 36 International Animal Health Journal

removed from the animals that provide food and fibre, we share our lives with companion animals ever more closely. With this change, the nature and goals of animal health research have also changed significantly. Animal health researchers are now studying animal disease in the context of improving the health and wellbeing of animals as a primary goal. This change also opens the door to comparative medicine. Our companion animals share almost every aspect of our lives, including exposures, and they are at risk for many of the same diseases as humans. For these reasons, they hold tremendous potential to inform disease risk in human health. As biomedical technology and computational capacity continue to improve, the nature and sophistication of observational studies will continue to evolve, and the time required to move discoveries from the bench into practice will decrease. As technologies such as –omic assays become more precise, applied research can use these tools to identify disease mechanisms (thus getting closer to identifying the etiology of disease), improve diagnostic testing, and optimise treatments for many different diseases. Veterinary research is poised to be in the vanguard as these technologies become more common. REFERENCES 1. Vickers AJ. How to randomize. J Soc Integr Oncol 2006; 4(4): 194-8. 2. Escobar LE, Peterson AT, Papes M, et al. Ecological approaches in veterinary epidemiology: mapping the risk of bat-borne rabies using vegetation indices and night-time light satellite imagery. Vet Res 2015; 46: 92. 3. Rohr JR, Raffel TR, Romansic JM, McCallum H, Hudson PJ. Evaluating the links between climate, disease spread, and amphibian declines. Proc Natl Acad Sci U S A 2008; 105(45): 17436-41. 4. Delesalle C, de Bruijn M, Wilmink S, et al. White muscle disease in foals: focus on selenium soil content. A case series. BMC Vet Res 2017; 13(1): 121. 5. Willcox JL, Hammett-Stabler C, Hauck ML. Serum 25-hydroxyvitamin D concentrations in dogs with osteosarcoma do not differ from those of age- and weight-matched control dogs. Vet J 2016; 217: 132-3. 6. Guy MK, Page RL, Jensen WA, et al. The Golden Retriever Lifetime Study: establishing an observational cohort study with translational relevance for human health. Philos Trans R Soc Lond B Biol Sci 2015; 370(1673).

Dr Missy Simpson Intramural research scientist at Morris Animal Foundation and the epidemiologist for Morris Animal Foundation’s Golden Retriever Lifetime Study. Her area of expertise is edpiemiology. She has authored peer-reviewed publications pertaining to epidemiologic research. Email: msimpson@morrisanimalfoundation.org

Volume 4 Issue 3


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International Animal Health Journal 37


CLINICAL STUDIES

How to Reduce Mycotoxin – induced Vaccination Failure Immunotoxic Substances such as Mycotoxins are Unsuspected Players in the Failure of Vaccines to Provoke a Proper Immune Response. Vaccines are commonly used to prevent various pathogenic challenges of viral, bacterial, and protozoan origins that usually lead to diseases affecting health and performance of livestock. Some of the disease challenges in swine where vaccines play a crucial role in preventing and controlling are listed in Table 1.

The Immune Response Two different mechanisms are involved in establishing an immune response: the inflammatory and acquired immune responses. The Inflammatory Response Inflammation is a non-specific response that occurs very rapidly and leads to the activation of phagocytes (macrophages and neutrophils). The activated phagocytes secrete many different molecules such as cytokines (involved in the recruitment and the activation of other cells). The Acquired Immune Response Acquired immune responses are associated with immunogenic memory carried out by B cells (humoral) and memory T cells (cellular). These cells are generated from naïve precursor cells after exposure to the microbial antigens. Upon interaction with the antigen presenting cells, B cells start to secrete specific antibodies. Naïve T cells rapidly proliferate and differentiate into effector T cells which target the host cells infected by pathogens.

Table 1. Swine diseases commonly addressed through vaccination.

Three Types of Vaccines There are two major types of vaccines normally used in swine production – live and inactivated – while other types of vaccines are seldom used. Live, Attenuated Vaccines Live-type vaccines contain either virus or bacteria in small amounts with the objective to infect the host and multiply in its body to produce immunity, preferably with minimal reaction. This leads to the recognition of increased amounts of the same type of pathogen by the host’s immune system, thus resulting in an enhanced immune response. Inactivated/Killed Vaccines Inactivated/killed vaccines have inactivated and processed virus or bacteria which then stimulates the immune system for a longer period of time inside the host. Inactivated vaccines are usually combined with an adjuvant (an oil or aluminum hydroxide) to increase their stability, and to stimulate the host immune response. Other These include toxoids (contain inactivated toxin of a bacterial pathogen), subunits/conjugates (contain pieces of the pathogen they protect against), and recombinant (contain virus with gene code for a vaccine protein against another virus) vaccines. Autogenous vaccines (autovaccines) are for therapeutic use, individually tailored for a host, made from cultures of pathogens isolated from the infection site. 38 International Animal Health Journal

This phase of proliferation is followed by a contraction phase during which about 90% of the effector T cells die, whereas the remaining cells differentiate into memory T cells. Thus, the immune response is highly complex and various cells interact with one another to produce the desired effect. Causes and Consequences of Vaccination Failure Factors leading to higher rates of vaccination failure result either from 1) a failure to provide potent vaccines properly to the host or 2) immune suppression in the host. Vaccine delivery can be hampered by contamination, improper storage or procedural errors. The five factors causing immune suppression directly in the animal include stress, poor nutrition, infectious agents, maternal antibody interference, and mycotoxins. These major causes and corrective measures are listed in Table 2. The good news is that these factors can largely be overcome by employing good management practices, including proper vaccine storage, handling and training.

Table 2. Factors affecting vaccine efficacy and corrective measures. Volume 4 Issue 3


CLINICAL STUDIES

Stress (Physical or Psychological) Weaning, crowding, mixing, shipping, restraint, limit feeding, noise, and excess heat or cold are some of the common stressors proven to affect the immune response. Improper Nutrition Overfeeding or malnutrition can lead to impaired immune response as the nutritional cost of the activation and maintenance of acute immune response has been about 10% of dietary protein and 1.1 g/kg of metabolic body weight (BW) in pigs. Infectious Agents Certain infectious agents can predispose the animal to secondary bacterial infection by suppressing specific immune function. For example, PRRSv can increase the susceptibility to pneumonia in pigs.

Figure 3. Sub-clinical doses of FUM and DON result in decreased antibody production post-vaccination.

Maternal Antibody Interference Piglets without maternal antibodies can be vaccinated as early as one day of age. However, in herds where vaccination is routinely done, piglets will have circulating maternal antibodies that could block the immune response against the vaccine. Researchers have found that 60% of pigs vaccinated at three weeks of age were found seropositive three months later; five weeks of age had 62%; six weeks of age had 79%; seven weeks of age had 96%; eight weeks of age had 100%, and at nine weeks of age had 87%. Mycotoxins Mycotoxins induce immunosuppression by depressing T- and B-lymphocyte activity, suppressing antibody production, and impairing macrophage/neutrophil effector functions. This results in vaccine failure and predisposes the animal to secondary bacterial infections as well. Specific mycotoxins and their influence on vaccine failure follow. • Aflatoxin B1 has been reported as a cause of immunisation failure with Erysipelothrix rhusiopathiae • bacterins, and also increased the severity of coccidiosis infection. • Ochratoxin A increased the susceptibility of pigs to natural infection by Salmonella cholerasuis, Serpulina hyodysenteriae or Campylobacter coli. • T-2 toxin has been found to increase the susceptibility to Salmonella, Listeria monocytogenes, Staphylococcus aureus, and Cryptosporidium baileyi. • Deoxynivalenol (750 ppb) has been shown to increase Salmonella invasion 10 times in porcine epithelial cells, and is highly toxic to lymphocytes. • Fumonisin (500 ppb) has been found to increase the intestinal colonisation of hemolytic Escherichia coli in piglets. Fumonisin has also been found to inhibit cell proliferation and alter cytokine production. • The combination of deoxynivalenol and fumonisins, even at sub-clinical doses, can impair liver and intestinal integrity, resulting in impaired vaccine response (Figures 3 and 4). www.animalhealthmedia.com

Figure 4. Mycotoxins reduce the efficacy of pseudorabies vaccine in nursery pigs.

Summary Overall, proper vaccination programmes along with good management practices can help overcome most of the factors that cause vaccination failure. However, specific immunotoxic substances such as mycotoxins, while often overlooked, can inflict real harm and lead to higher treatment costs. Consequently, an effective and comprehensive mycotoxin risk management programme is advised.

Raj Murugesan Regional Technical Director at BIOMIN America. Email: magazine@biomin.net

Erika Hendel Swine Technical Manager at BIOMIN America. Email: magazine@biomin.net

International Animal Health Journal 39


MANUFACTURING AND PACKAGING

Breakthrough Cell-based Companion Animal Therapies: New Treatments Bring New Challenges In this day of expanding and revolutionary human health treatment options, it can get lost that animal health options, in particular companion animal health, often mimic the progress in the human arena. In the developed nations of the world, our pets are treasured members of our families. Whenever possible, we strive to provide them with the same level of care we would provide to our human family. Historically, treatments for a variety of illnesses and diseases were limited to small molecule and antibody-based treatments. These products generally do not require sophisticated temperaturecontrolled shipping packaging or methodologies. However, with the advent of new regenerative medicine techniques, particularly cell-based therapies, the paradigm for storage, shipping and other challenges regarding the maintenance of stability and ultimate cell viability have changed dramatically. Cell-based therapies most often need to be stored and transported at cryogenic temperatures in liquid nitrogen dry vapour shippers and stored in liquid nitrogen freezers. While cryogenically stored and transported large animal stem cell therapies have been a part of production herd and flock veterinary medicine for some time now, this is a largely a new challenge for the animal health companies developing cell-based therapies and for companion animal veterinarians. It is imperative for a manufacturer to choose a shipping solution that can address these issues. In particular, the cryogenically stored and transported stem cell therapies currently under development need to be stored and transported in liquid nitrogen (LN2). This requires specialised shippers called dewars that can maintain the -150C temps for the duration of shipment and beyond. These dewars come with high capital cost that needs to be contained. They are also difficult to track due to often non-traditional and varied shipping methods. Return logistics of these specialised shippers are also a constant struggle. Strong IT solutions can help track not only the dewars physically, but also the performance of the carriers transporting them – live and dynamic performance of the shippers themselves. IT solutions supporting desired return logistics of this shippers can help reduce the need for large fleet sizes often needed to support poor return rates on the shippers. Improved data logging solutions can accurately track and report in real time the chain of custody and chain of condition of the products contained within the shippers. This article will address particular issues surrounding the logistics and shipment of cryogenic animal health products, such as these new regenerative therapies, as they represent the highest level of need, both in terms of capital and shipping expense related costs, for any organisation working with these products. They also represent a higher level of resource needs for the end user where the shippers often end up serving as temporary storage units for the veterinary clinics treating their livestock with these critical stem cell therapies for herd/flock health. We will break the challenges into their core components and address 40 International Animal Health Journal

solutions individually. These critical issues, as we see them, are: • Initial validation and requalification every use of the shippers • Chain of custody and chain of condition of the shipper and stem cell/regenerative medicine payloads • Monitoring of integrator and speciality carrier performance to optimise product delivery and costs • Overall logistics expertise and ability to coordinate with multiple types of shipping partners • Return logistics for high value of capital asset shippers • Monitoring of shippers in the veterinary offices and clinics being used as temporary storage Initial Validation of Shippers and Requalification Every Use of the Shippers Cryogenic shippers, commonly known as dewars, are themselves commodities. Anyone can purchase and use them. No special expertise or skills are required. However, when transporting high-value temperature-controlled products such as animal health stem cell therapies, this requires more than just purchasing the dewar and sending it with traditional carriers. While the manufacturers do validate basic performance characteristics of their shippers, they do not do full validation to IATA and other international shipping standards. This should be done by the service provider chosen for logistics support by the animal health client. This validation should be done to USDA quality standards as well as new Good Distribution Practices (GDP). Another consideration in choosing a partner for cryogenic shipments is how they test and verify that for an individual shipment that the dewar will perform as required. To ensure performance, a shipper should be requalified each use. Most users only re-test performance of dewars quarterly, semi-annually or never. In these cases, there is no ability to predict and ensure that the valuable payload is safe and going to be maintained at the -150C or below temperatures. To ensure this, a dewar fleet should be serialised for individual tracking. This allows each shipper to be tested and performance tracked over time. This serialisation and subsequent performance tracking allows shippers with declining or failing hold times to be repaired or retired if needed to best protect these shipments where the payload can easily reach tens of thousands of dollars in catalogue value. This does not even begin to illustrate the total value of a lost shipment due to shipper failure to the supplier and end user of the stem cell therapy, in terms of time and/or livestock loss due to stem cell therapies not being available. Chain of Custody and Chain of Condition of the Shipper and Stem Cell Therapy Payload Traditional integrators (FedEx, UPS, DHL, etc.) and speciality couriers offering “white glove” transport services generally offer web-based tracking of point-to-point shipments. This is certainly key in monitoring shipments, but does not tell the equally, if not more important, story of the condition of the shipper and high-value stem cell therapy payload. Suppliers would be wise to choose a logistics partner who has strong IT and data logging solutions. This includes an Volume 4 Issue 3


CORPORATE PROFILE Corporate Profile

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International Animal Health Journal 41

International Animal Health Journal 11


MANUFACTURING AND PACKAGING

integration with transporter software to pull all relevant data into one dashboard for the stem cell therapy supplier to view as needed. Even more important is a total IT and data logging solution that tracks position, internal and external temperature, dewar orientation (critical to maintaining hold times) and shock events, and does so in real time. This is critical as it allows for the software solution to not only track these parameters, but to be able to set alarms and notifications to the logistics provider and others when any of these data points move beyond acceptable ranges. With this data, intervention can be attempted before the shipper warms and the product is lost. Without it, if an adverse shipping event occurs in regard to payload integrity it will only be known after the fact and product is lost. As was discussed earlier, the real cost of a lost payload goes well beyond the sticker price of the product. Monitoring of Integrator and Speciality Carrier Performance to Optimise Product Delivery and Costs In choosing a logistics provider, an important factor is to find someone who is carrier-agnostic. So what does that mean? It means the solution provider is able to use, and track the performance of, each carrier. No one carrier performs at peak levels in all shipping lanes. An IT solution that tracks, by shipping lane, the cost, on-time performance and more should be available. A stem cell therapy manufacturer needs to be able to pick the optimal carrier for each leg of shipment, to ensure the best delivery performance to the end user. This carrier performance data collection is a key part of the IT solution the logistics solution provider provides to the stem cell therapy supplier/manufacturer for consideration in carrier choice. The ability to make shipping decisions in this manner allows for best practice in delivery to clients and reduces costs, not only in initial decisionmaking, but on an ongoing basis. This constant ability to refine logistics lends the best value to all involved. 42 International Animal Health Journal

Overall Logistics Expertise and Ability to Coordinate with Multiple Types of Shipping Partners In evaluating a possible logistics services partner, one should think carefully about their level of experience in worldwide shipping logistics. As mentioned earlier, this includes having a carrier-agnostic philosophy to be impartial in recommending carriers, but this is only part of the solution. Other key factors to be considered in choosing a provider include, but are not limited to: • Experience with various different temperature-controlled products • Number of countries where they have experience shipping temperature-controlled products • Individual lane performance data and reporting by location and carrier • Considerable experience with variety of dewar types in order to help choose optimal shipper for different shipping lane challenges • Strong operational relationships with all major carrier options. This can be critical when transit intervention is needed for customs delays, shipper integrity issues, etc. Once again, a strong IT solution to track performance of carriers and integrate with their systems is key. This allows the chosen logistics provider to serve in a truly consultative role with the stem cell therapy manufacturer, both initially and dynamically throughout the relationship. Choosing a logistics provider with a long and varied experience with cryogenic products and a robust IT infrastructure will lend the greatest value to the stem cell therapy manufacturer. Return Logistics for High Value of Capital Asset Shippers Historically, animal health stem cell therapy manufacturers have purchased and maintained their own fleet of cryogenic Volume 4 Issue 3


MANUFACTURING AND PACKAGING shippers. These fleets come with high capital costs as dewars can cost up to $5000 USD each. For large-scale stem cell therapy makers, the needed fleet size to distribute their products worldwide can number in the thousands of units, resulting in tens of millions of dollars in upfront capital expenditures. If the return logistics of these costly shippers is not managed well, low return rates will necessitate larger fleets, without which there will be low availability for future shipments. Also, typically stem cell therapy manufacturers have poor internal resources and IT systems to manage return logistics, generally resulting in higher lost dewar rates and the need for continued replacement of dewars on an ongoing basis. This can easily add millions of additional dollars in capital expenditures every year. Even worse, without predictable return of shippers for re-use, there is no ability to reliably budget for this additional capital cost. In partnering with an experienced cryogenic logistics solutions provider, with a robust IT tracking system, these costs can be managed efficiently and minimised. In addition, this results in the need for smaller fleets and lower upfront capital expenditures. The improved return logistics will then result in lower annual capital fleet replacement costs as well. As mentioned earlier, a logistics provider with a strong ability to serialise and assess dewars and requalify each use, repairing or replacing shippers as needed and tracking via their IT platform, allows these capital costs to be constantly evaluated for opportunities for reduction and managed most effectively. An optimal logistics solution partner can also use their IT platform that tracks carrier performance and cost to choose the most efficient and cost-effective carrier for the return shipping segments to aid in more effectively managing those variable expenses as well. Monitoring of Shippers in the Field Being Used as Temporary Storage A unique component in the field of animal health stem cell therapies may be use of the dewars as temporary storage units by the veterinary clinics. This is related to challenges in return logistics of the shippers, but presents other challenges for the stem cell therapy manufacturer as well. Customer adoption of companion animal stem cell therapy will also likely be based on ease of use and storage. The dewars have limited hold times of 10 days, depending on size and configuration. Many stem cell therapy suppliers may need to offer services to refill the shippers with liquid nitrogen at set intervals for larger volume clients to enable volume storage. However, this is a costly service and without a strong ability, via condition-monitoring data loggers, and the IT platform to collect and monitor that data, dewars may be refilled with liquid nitrogen unnecessarily or, worse yet, go warm before being refilled, resulting in significant product losses. All of the above create higher distribution cost of the stem cell therapies and potential veterinarian failure. A logistics partner that can either provide directly, or work closely with companies that can recharge dewars in the clinics with liquid nitrogen, offers an invaluable service to the animal health stem cell therapy company. The ability to track location and monitor the condition of dewars with a robust IT solution that previously was not possible, can result in higher-end stem cell therapy user satisfaction with their provider. The resulting satisfaction reduces customer loss rates and can improve new customer acquisition. In summary, in choosing a logistics provider of cryogenic shipping services for animal products, there are several key www.animalhealthmedia.com

factors to consider. One should be looking for a partner with the strongest possible IT solution that helps accomplish and track the following: • The most stringent dewar fleet validation and requalifying processes • The ability to precisely track the chain of condition and chain of custody of their valuable stem cell therapies • A carrier-agnostic approach and the database to track individual carrier performance on any shipping lane globally • Extensive general worldwide logistics experience with multiple cryogenic products • Strong ability to manage return logistics of high-cost capital dewar assets • Good working relationships with providers of liquid nitrogen refill services for field storage of stem cell therapies in cryogenic shippers Cryogenic distribution and shipping of stem cell therapy products comes with many challenges and issues not faced by products stored and shipped at other temperature ranges. The needed solutions regarding the associated logistics are somewhat rare skill sets, but they do exist. Critical examination of potential partners will provide a vast improvement in capital cost management, end user satisfaction and prevention of product loss and associated costs.

Kirk Randall the Sales Director at Cryoport. He has more than 25 years of successful sales and business development experience and over 17 years of creating and implementing preclinical and clinical drug development plans with large pharmaceutical and biotech companies. Email: krandall@cryoport.com

International Animal Health Journal 43


LIVESTOCK

Dietary Strategies Protecting Heat-stressed Farm Animals Against Increased Susceptibility to Inflammatory Diseases

Global warming and the growing consumer demand for animal-derived food and meat, particularly in newly industrialising countries with hot climates, raise public concerns on animal welfare, long-term sustainable livestock production and food and consumer safety (see Figure 1). In these areas, heat stress is one major reason for economic losses in livestock production. Besides lowering the quality of forage and feedstuffs, a hot and humid climate reduces reproduction performance and productivity of livestock animals. Moreover, heat stress affects general health and the susceptibility of farm animals to infectious diseases. In addition, new pathogens or vectors may be introduced into areas with changing climate.

Under heat stress, animals alter their behaviour and physiology in order to dispose of heat and to decrease body temperature (see Figure 2). They spend less time feeding and moving, while spending more time on resting, drinking and panting. Obvious signs of heat stress in livestock include the decrease in feed intake and daily gain, the deterioration of product quality (meat, eggs and milk), and the increase in morbidity and mortality.

Figure 2. Heatstress index for growing-finishing pigs. Source: Iowa State University

To address and counteract these challenges, a detailed knowledge of the physiological mechanisms of heat stress in livestock species is required. Consequently, the purpose of this article is to provide a brief overview on heat stressinduced physiological and molecular changes in livestock. Figure 3 summarises direct and indirect heat stressinduced consequences for livestock.

Figure 1. Development of average meat consumption within 15 years depending on different regional areas (modified after FAO).

Figure 3. Heat stress reduces performance of livestock animals due to various direct and indirect negative influences. 44 International Animal Health Journal

Volume 4 Issue 3


LIVESTOCK Intestinal Morphology The results of studies reporting on heat stress-induced changes in intestinal morphology are not consistent. Thus, contradictory information on the alteration of villus height and crypt depth, two key parameters for the intestinal capacity of nutrient absorption, exist. For instance, Song et al. (2014) found a reduction of villus height and an increase in crypt depth in the jejunum of Ross 308 broilers, exposed to cyclic heat stress. Other studies reported on a reduced ileal crypt depth, but discovered no changes in villus height of Ross 308 broilers kept at 30°C compared to their littermates kept at 23°C (Burkholder et al., 2008). In heat-stressed pigs, Pearce et al. (2015) observed a villus height reduction in tendency, but found no changes in crypt depth. In conclusion, the differing and contradictory results regarding gut morphology may reflect differences in the applied heatstress regimes and/or species- and breedspecific differences. Metabolic Changes The initial cellular response to heat stress seems to consist of an increase in energy expenditure. For this purpose, mitochondrial activity is increased to produce sufficient amounts of ATP for essential cellular processes, like Na+/ K+-ATPase activity. The up-regulation of mitochondrial capacity is linked to a higher production of reactive oxygen species, resulting in an increased level of endogenous oxidative stress (Akbarian et al., 2016). As a consequence, heat-mediated oxidative stress produces alterations in cell signalling, affecting heat shock protein expression (HSP) as well as damage to the intestinal barrier (Lambert et al., 2002) and hyperthermia-induced apoptotic cell death (Katschinski et al., 2000). The up-regulated expression of HSPs is an endogenous mechanism conferring cells protection against stress. For instance, HSP70 has been shown to protect intestinal mucosa of heat-stressed broilers by improving antioxidant capacity and inhibiting lipid peroxidation (Gu et al., 2012). A study with rats has provided evidence for the increased energy consumption during hyperthermia. In this study, liver glycogen levels declined by about 20% after exposure to heat stress for two hours (Hall et al., 2001). Whole-body hyperthermia induces re-distribution of blood from internal organs to the periphery to intensify heat loss from the body (Lambert et al., 2002). Due to this shift, cellular hypoxia and metabolic stress are induced in the intestinal tract (Hall et al., 2001). Since heat stress affects in particular the insulin signalling pathway, changes in whole-body energy metabolism are partially caused through changes in glucose uptake and metabolism. This hypothesis is supported by the results of several studies, showing an increased intestinal glucose uptake in heatstressed animals (e.g. Pearce et al., 2013; Fernandez et al., 2015). Different other tissues might also show alterations in individual glucose uptake and utilisation. In this context, Fernandez et al. (2015) observed a higher insulin receptor substrate-1 abundance in skeletal muscle, but not in adipose tissue of pigs. The differential effects of heat stress in various tissues might ultimately induce changes in energy deposition and cause shifts in lean body mass of the animals. This phenomenon was described for postnatal body composition of dams exposed to heat stress during gestation. Piglets from sows exposed to heat stress (28°C to 34°C) during the first half of gestation showed a reduced longissimus dorsi cross-sectional area and an increased subcutaneous fat thickness and blood insulin concentrations, compared to piglets from sows kept under normal temperature conditions (18°C to 22°C) (Boddicker et al., 2014). Interestingly, Fernandez et al. (2015) reported www.animalhealthmedia.com

on increased insulin receptor substrate-1 abundance in skeletal muscle but not in adipocytes, suggesting a higher energy uptake into the muscle but not fat tissue. In summary, these results suggest that further research is needed to evaluate the detailed mechanism as to how heat stress-induced metabolic changes in dams cause an increased fat deposition in piglets. Intestinal Barrier Integrity One explanation for an increased susceptibility to diseases of livestock animals under heat stress consists in the occurrence of an impaired intestinal barrier function. The intestinal barrier is the first-line defence against harmful microbial pathogens, their toxins and antigens from the intestinal lumen. The intestinal barrier is formed by a layer of epithelial cells, and the cellular interspaces are sealed by tight junctions, which are mainly composed of proteins of the claudin and the occludin family. Tight junctions act as selective barriers regulating the paracellular transport. Heat stress compromises the integrity of the tight junctions and thereby increases the permeability of the intestinal mucosa, disturbing its originary function in absorbing nutrients and keeping pathogens at bay. Measurement of the transepithelial electrical resistance (TEER) is routinely used to determine this integrity, respectively the permeability of the intestinal barrier in freshly obtained intestinal samples or cell cultures. The lower the TEER, the higher the degree of impairment of the intestinal barrier integrity. It has been shown that heat stress reduces the TEER in Caco-2 monolayers (Xiao et al., 2013), but also in pigs in vivo (Sanz Fernandez et al., 2013). In the literature, numerous studies report on the gene- or protein-expression of tight junction proteins under heatstress conditions. For instance, Xiao et al. (2013) have detected in Caco-2 an increase in occludin mRNA and protein levels when culture temperature of the cells was raised from 37°C to 41°C. In contrast, increasing the temperature up to 43°C reduced Zonula occludens-1 mRNA- and protein-expression, whereas no changes in claudin-2 abundance could be observed (Xiao et al., 2013). Exposition of broilers to heat stress at 33°C for 10 h resulted in a significant decrease of occludin and Zonula occludens-1 protein levels (Song et al., 2014). In pigs, colonic occludin gene abundance has been found to be decreased under heatstress conditions (Pearce et al., 2015). In contrast, claudin-3 and occluding protein expression increased in the ileum of growing pigs under heat stress (Pearce et al., 2013). In summary, these studies demonstrate that temperature influences tight junction protein expression. Although in most of the studies, tight junction protein abundance was decreased by heat stress due to damage and loss of function, others have shown an upregulation of their gene expression. This phenomenon may be explained as a direct consequence of the heat stress: the upregulation of tight junction gene expression might serve as an intestinal barrier function to counter-regulate the loss of tight junction proteins induced by heat stress. International Animal Health Journal 45


LIVESTOCK

Figure 4. Temperature-induced reduction of tight junction protein abundance (Modified after Dokladny et al., 2016). A) Intact tight junction barrier at thermoneutral ambient temperature. B) Heat stress-induced breakdown of tight junctions C) Upregulation of tight junction gene expression to counteract heat stress-afflicted damage of intestinal barrier. For details read Dokladny et al. (2016).

In conclusion, the results of all studies investigating the link between heat stress and intestinal barrier integrity unambiguously demonstrate the negative impact of heat stress on the intestinal barrier. The impairment of the intestinal barrier integrity results in an increased permeability of the gut to different molecules and pathogens. Consequently, increased concentrations of substances from the gut can be found in the blood of the animals. For example, blood endotoxin levels in heatstressed pigs increased by 200 % when compared to pigs kept under normal temperature conditions (Pearce et al., 2013). Comparing the effect of prolonged heat stress to short-term exposure have shown also remarkable differences in endotoxin blood levels. Gilts exposed to 35°C for seven days showed 260-390% increased blood endotoxin levels compared to gilts exposed to heat stress at 35°C only for 24 hours (Sanz Fernandez et al., 2013). The increased endotoxin levels under heatstress exposure can cause a systemic inflammatory response, resulting in decreased growth performance and increased morbidity and mortality (Xu et al., 2015; Dokladny et al., 2008). Increased migration of bacteria from the gut to other parts of the body could be directly demonstrated by QuinteiroFilho et al. (2012). In their study, broilers infected with Salmonella enteriditis showed a decreased performance and were linked to 3.9-times higher Salmonella counts in the spleen of heat-stressed animals (31°C), compared to control animals (21°C). Intestinal Microbiota Heat stress has been shown to affect the composition of the intestinal microbiota in several recent studies. In Holstein heifers, an increase of environmental temperature from 20°C to 33°C induced significant changes to the major phylogenetic groups in the rumen, accompanied by a reduction of short-chain fatty acid (SCFA) production (Tajima et al., 2017). These changes could be related to the 46 International Animal Health Journal

reduced dry matter intake of the animals under heat stress. Changes in SCFA production due to heat stress have been also observed in pigs, although in this study, overall SCFA production was not reduced. However, the proportion of the different SCFAs was altered to a higher percentage of acetate and a lower abundance of propionate (Song et al., 2011). A change in the proportion of produced SCFA might reflect both a shift in the metabolic activity of bacteria and/ or a changed composition of the intestinal microbiota. It has been also shown that heat stress directly alters the intestinal microbial diversity. In this context, Burkholder et al. (2008) observed a reduced ileal microbial diversity in broilers kept at 30°C compared to broilers kept at 23°C. Another study with poultry showed the context between heat stress and changes in some bacterial groups in more detail. Cyclic heat stress decreased the counts of Lactobacilli and Bifidobacteria in the small intestine, whereas time counts of coliforms and Clostridium increased (Song et al., 2014). This might reflect an unfavourable change, since numerous members of the lactobacilli- and bifidobacterial families are considered as advantageous for the host. Although most coliforms and clostridia are commensal members of the gut microbiota, some of them are associated with proteolytic fermentation, and contain a range of potential pathogenic members (e.g. C. perfringens, Salmonella or endotoxin producing E. coli). Consequently, increased counts of these bacterial groups might result in increased production of potentially harmful fermentation products and proliferation of potential pathogens. Immune System Heat stress leads to an overall immunosuppression in livestock, representing another possible mechanism explaining the increased susceptibility of animals to illnesses. In poultry, heat stress suppresses the innate and adaptive immunity. Broilers under heat stress have shown lower levels of total circulating antibodies, as well Volume 4 Issue 3


Using the power of nature: Phytogenics as safe and natural performance enhancers delacon.com

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International Animal Health Journal 47


LIVESTOCK as lower specific IgM and IgG levels against Newcastle disease virus and infectious bursal disease virus (Niu et al., 2009; Akhavan-Salamat et al., 2016; Sohail et al., 2010). Exposure of chickens to a high temperature also decreases the percentage of CD4+ T cells and CD8+ T cells, which impairs the cellular immune response (Khajavi et al., 2003; Trout and Mashaly, 1994). Moreover, heat stress has a negative impact on intestinal mucosal immunity. The intestinal mucosa is an important barrier against pathogen invasion. A mucus layer covers the luminal epithelium, and the lamina propria tissue below harbours a wide range of immune cells, including intraepithelial lymphocytes, regulatory T cells, secretory IgA cells and others. Under heatstress conditions, the integrity of the mucosal epithelial cells is compromised, allowing bacteria and other antigens to invade into the lamina propria. The massive invasion of antigens triggers inflammatory processes. The expression of IL-10 and IL-4 from the intestinal mucosa has been shown to decrease in heat-stressed animals, indicating an impairment of anti-inflammatory function and immune cell proliferation. Additionally, the expression of Tolllike receptors decreases, reflecting attenuation to resist bacterial invasion (Liu et al., 2012). Also in swine, heat stress has been demonstrated to influence cellular immunity. Exposure to heat stress reduced the proliferation of porcine T cells in peripheral blood (Kelley, 1985). Jensen et al. (1983) found that phytohemagglutinin skin-test reaction was weakened in barrows under heat stress, which is a reliable indicator for assaying cellular immunity. Heat stress also has been shown to cause neutrophil infiltration in ileum and inflammation, which worsens the integrity of the intestinal barrier (Pearce et al., 2013). Conclusion • Heat stress has multiple etiological factors causing physiological, behavioural and metabolic changes. • Heat stress has substantial effects on the immune system, causing suppression of immunity and reduction of the ability to resist pathogen invasion. This results in a higher morbidity and mortality. • Heat stress reduces the intestinal absorption surface (villi height), resulting in lower nutrient utilisation and higher substrate for fermentation. • Heat stress severely alters signalling pathways, regulating major processes of glucose and lipid metabolism, resulting in unfavourable changes in the relation of protein and fat deposition. • Heat stress triggers the proliferation of undesired bacteria, resulting in higher numbers of proteolytic bacteria and potential pathogenic bacteria. • Heat stress decreases intestinal barrier integrity, resulting in the invasion of a higher number of antigens and pathogens into the bloodstream and the organism. • Heat stress-induced changes in the organism represent a complex of the above-mentioned symptoms (=syndrome), resulting in a strong general impairment of animal performance and health. REFERENCES 1. Akbarian, A., Michiels, J., Degroote, J., Majdeddin, M., Golian, A., De Smet, S. 2016. Association between heat stress and oxidative stress in poultry; mitochondrial dysfunction and dietary interventions with phytochemicals. Journal of Animal Science and Biotechnology 7:37. DOI: 10.1186/ s40104-016-0097-5. 2. Akhavan-Salamat, H., Ghasemi, H. 2016. Alleviation of chronic heat stress in broilers by dietary supplementation of betaine and turmeric rhizome powder: dynamics of performance, leukocyte profile, humoral immunity 48 International Animal Health Journal

and antioxidant status. Tropical Animal Health and Production 48: 181-188. 3. Boddicker, R.L., Seibert, J.T., Johnson, J.S., Pearce, S.C., Selsby, J.T., Gabler, N.K., Lucy, M.C., Safranski, T.J., Rhoads, R.P., Baumgard, L.H., Ross, J.W. 2014. Gestational Heat Stress Alters Postnatal Offspring Body Composition Indices and Metabolic Parameters in Pigs. PLOS One 9(11): e110859. https://doi.org/10.1371/journal.pone.0110859. 4. Burkholder, K.M., Thompson, K.L., Einstein, M.E., Applegate, T.J., Patterson, J.A. 2008. Influence of stressors on normal intestinal microbiota, intestinal morphology, and susceptibility to Salmonella enteritidis colonization in broilers. Poultry Science 87(9):1734-41. doi: 10.3382/ ps.2008-00107. 5. Dokladny, K., Zuhl, M.N., Moseley, P.L. 2016. Intestinal epithelial barrier function and tight junction proteins with heat and exercise. Journal of Applied Physiology 120(6):692 – 701. doi: 10.1152/japplphysiol.00536.2015. 6. Dokladny, K., Ye, D., Kennedy, J.C., Moseley, P.L., Ma, T.Y. 2008. Cellular and Molecular Mechanisms of Heat Stress-Induced Up-Regulation of Occludin Protein Expression – Regulatory Role of Heat Shock Factor-1. The American Journal of Pathology 172(3):659–670. doi: 10.2353/ajpath.2008.070522. 7. Fernandez, M.V.S., Stoakes, S.K., Abuajamieh, M., Seibert, J.T., Johnson, J.S., Horst, E.A., Rhoads, R.P., Baumgard, L.H. 2015. Heat stress increases insulin sensitivity in pigs. Physiological Reports 3(8): e12478. doi: 10.14814/ phy2.12478. 8. Fernandez, M.V.S., Johnson, J.S., Abuajamieh, M., Stoakes, S.K., Seibert, J.T., Cox, L., Kahl, S., Elsasser, T.H., Ross, J.W., Isom, S.C., Rhoads, R.P., Baumgard, L.H. 2015 9. Gu, X.H., Hao, Y., Wang X.L. 2012. Overexpression of heat shock protein 70 and its relationship to intestine under acute heat stress in broilers: 2. Intestinal oxidative stress. Poultry Science 91 :790–799. http://dx.doi.org/ 10.3382/ ps.2011-01628. 10. Hall, D.M., Buettner, G.R., Oberley, L.W., Xu, L., Matthes, R.D., Gisolfi, C.V. 2001. Mechanisms of circulatory and intestinal barrier dysfunction during whole body. American Journal of Physiology – Heart and Circulatory Physiology 280(2):509-521. 11. Jensen, MA., Blecha, F., Hines, R. 1983. Effect of fluctuating hot temperatures on performance and immunity in finishing pigs. Kansas Agricultural Experiment Station Research Reports 10: 106-109. 12. Katschinski, D.M., Boos, K., Schindler, S.G., Fandrey, J. 2000. Pivotal role of reactive oxygen species as intracellular mediators of hyperthermia-induced apoptosis. Journal of Biological Chemistry 275(28):21094-8. doi: 10.1074/ jbc.M001629200. 13. Kelley, K. 1985. Immunological consequences of changing environmental stimuli. In: Moberg. G.P. (Ed.). Animal Stress. American Physiological Society, Bethesda, MD. 14. Khajavi, M., Rahimi, S., Hassan, Z., Kamali, M., Mousavi, T. 2003. Effect of feed restriction early in life on humoral and cellular immunity of two commercial broiler strains under heat stress conditions. British Poultry Science 44: 490-497. 15. Lambert, G.P., Gisolfi, C.V., Berg, D.J., Moseley, P.L., Oberley, L.W., Kregel, K.C. 2002. Selected contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress. Journal of Applied Physiology 92: 1750–1761, 2002. 16. Liu, X., Li, H., Lu, A., Zhong, Y., Hou, X., Wang, N., Jia, D., Zan, J., Zhao, H., Xu, J., Liu, F. 2012. Reduction of intestinal mucosal immune function in heat-stressed rats and bacterial translocation. International Journal of Hyperthermia 28: 756-765. 17. Niu, Z., Liu, F., Yan Q., Li, W. 2009. Effects of different levels Volume 4 Issue 3


LIVESTOCK of vitamin E on growth performance and immune responses of broilers under heat stress. Poultry Science 88: 2101-2107. 18. Pearce, S.C., Mani, V., Boddicker, R.L., Johnson, J.S., Weber, T.E., Ross, J.W., Rhoads, R.P., Baumgard, L.H., Gabler, N.K. 2013. Heat Stress Reduces Intestinal Barrier Integrity and Favors Intestinal Glucose Transport in Growing Pigs. PLoS ONE 8(8): e70215. https://doi.org/10.1371/journal. pone.0070215. 19. Pearce, S.C., Sanz Fernandez, M.V., Torrison, J., Wilson, M.E., Baumgard, L.H., Gabler, N.K. 2015. Dietary organic zinc attenuates heat stress-induced changes in pig intestinal integrity and metabolism. Journal of Animal Science 93:4702–4713. doi: 10.2527/jas.2015-9018. 20. Quinteiro-Filho, W.M., Gomes, A.V., Pinheiro, M.L., Ribeiro, A., Ferraz-de-Paula, V., Astolfi-Ferreira, C.S., Ferreira, A.J., Palermo-Neto, J. 2012. Heat stress impairs performance and induces intestinal inflammation in broiler chickens infected with Salmonella enteritidis. Avian Pathology 41(5):421-7. doi: 10.1080/03079457.2012.709315. 21. Sanz Fernandez, M.V.S., Pearce, S.C., Gabler, N.K., Patience, J.F., Wilson, M.E., Socha, M.T., Torrison, J.L., Rhoads, R.P., Baumgard, L.H. 2013. Effects of supplemental zinc amino acid complex on gut integrity in heat-stressed growing pigs. Animal 8:1:43–50. doi:10.1017/S1751731113001961. 22. Sohail, M., Ijaz, A., Yousaf, M., Ashraf, K., Zaneb, H., Aleem, M., Rehman, H. 2010. Alleviation of cyclic heat stress in broilers by dietary supplementation of mannanoligosaccharide and lactobacillus-based probiotic: Dynamics of cortisol, thyroid hormones, cholesterol, C-reactive protein, and humoral immunity. Poultry Science 89: 1934-1938. 23. Song, R., Foster, D.N., Shurson, G.C. 2011. Effects of feeding diets containing bacitracin methylene disalicylate to heat-stressed finishing pigs. Journal of Animal Science 89(6):1830-43. doi: 10.2527/jas.2010-3218. 24. Song, J., Xiao, K., Ke, Y.L., Jiao, L.F., Hu, C.H., Diao, Q.Y., Shi, B., Zou, X.T. 2014. Effect of probiotic mixture on intestinal microflora, morphology, and barrier integrity of broilers subjected to heat stress. Poultry Science 93: 581-588. 25. Tajima, K., Nonaka, I., Higuchi, K., Takusari, N., Kurihara, M., Takenaka, A., Mitsumori, M., Kajikawa, H., Aminov, R.I. 2017. Influence of high temperature and humidity on rumen bacterial diversity in Holstein heifers. Anaerobe 13: 57-64. 26. Trout, J., Mashaly, M. 1994. The effects of adrenocorticotropic hormone and heat stress on the distribution of lymphocyte populations in immature male chickens. Poultry Science 73: 1694-1698. 27. Xiao, G., Tang, L., Yuan, F., Zhu, W., Zhang, S., Liu, Z., Geng, Y., Qiu, X., Zhang, Y., Su, L. 2013. Eicosapentaenoic acid enhances heat stress-impaired intestinal epithelial

barrier function in Caco-2 cells. PLoS One 8: e73571. 28. Xu, Q., Guo, X., Liu, J., Chen, B., Liu, Z., Su, L. 2015. Blockage of protease-activated receptor 1 ameliorates heatstress induced intestinal high permeability and bacterial translocation. Cell Biology International 39: 411-417.

Tobias Aumiller He received his diploma in Technical Biology before switching to Agricultural Sciences in 2011. He completed his Ph.D. in animal nutrition at the University Hohenheim in 2015, focusing on feed-gut-microbiota interaction. The same year he joined Delacon as Manager to coordinate research and development tasks for Swine and Microbiology. Email: tobias.aumiller@delacon.com

Xiaodan Zhou She holds a bachelor degree in Animal Sciences from the Sichuan Agricultural University and a master degree in Animal Nutrition from the Chinese Academy of Agricultural Sciences. In 2014, she received a doctoral degree in Agricultural Sciences from the Justus-Liebig University Giessen, Germany. In 2016, she joined Delacon as R&D Manager Poultry and Immunology. Email: emiliy.zhou@delacon.com

Ester Vinyeta She started her professional career as lecturer and researcher on crop and food production at the Universitat de Vic in Barcelona in 1992. In 2002, she moved to Esporc S.A. as nutritionist and technical director of three feed mills. After years of work as researcher at Scothorst Feed Research and at Buhler AG, she took over the part of Species Leader Swine and feed technology expert at Delacon in 2014. Email: ester.vinyeta@delacon.com

Andreas S. Müller

Jan Dirk van der Klis

He continued his career after the completion of his PhD thesis in Nutritional Sciences as an Assistant Professor and Junior Professor at the Universities in Giessen and Halle/ Saale (both Germany). Since 2008 he holds an University Habilitation in „Nutrition Physiolgoy and Animal Nutrition“. In 2013 he joined Delacon, where he is today responsible for research regarding product improvement and development of new products as Head of Research & Development.

He started his career in poultry nutrition in 1987 at Spelderholt Institute in the Netherlands and completed his Ph.D. in animal nutrition at the Wageningen Agricultural University in 1993. He worked for several research institutes in the Netherlands. During his prior 8-year profession he was consulting nutritionists at feed mills worldwide. In 2014 he joined Delacon as Species Leader Poultry and works today as Director of Products & Innovation.

Email: andreas.mueller@delacon.com

Email: jandirk.vanderklis@delacon.com

www.animalhealthmedia.com

International Animal Health Journal 49


LIVESTOCK

Heat Detection in Dairy Cows: A Review of Methods with an Emphasis on Those Utilising Milk The widespread global replacement of bulls with artificial insemination (AI) means that accurate detection and timing of oestrus (heat detection) becomes a critical activity. Traditional observation of behavioural signs have been re-evaluated (Back et al., 2014), but these methods rely on regular visual observation of cows and an environment conducive to demonstration of oestrus behaviour; for example, traditional tie stalls seen in some European countries are associated with reduced behavioural signs (Reviewed by Walsh et al., 2011). Some cows fail to exhibit behaviour associated with oestrus (so called silent heats) (Esslemont, 1973). While measuring progesterone in milk fat in 123 cows from a number of farms, Claus et al. (1983) concluded that the greatest influence on cow fertility was management, with 32% of cycles detectable by progesterone not being recognised by herdsmen. Additionally, between 5% and 21% of cows were inseminated at the incorrect time in the cycle (Claus et al., 1983). Dairy cow fertility has been declining internationally (Gonzalez-Recio et al., 2004; Mee, 2007) with subfertility being identified as the most important reason for culling, and the economic costs of subfertility being second only to mastitis (Mee, 2007). Additionally, genetic correlations between milk yield and reproductive measures in dairy cows are generally unfavourable (Pryce et al., 2004). While Boyd (1992) revealed in studies that 95% of cows had active ovaries, Lopez et al. (2005) showed that for Holstein breeds, the number was lower at 71%. In the 1980s, researchers aimed to take management of bovine fertility into the field and achieve â&#x20AC;&#x153;on-farm fertility controlâ&#x20AC;? (Foulkes et al., 1982). Since that time a wide variety of techniques and devices have been proposed and tested to improve oestrus detection (Mottram, 2015). Frequently the performance of a device is compared with the ability of the herdsman to observe behavioural indications of oestrus, or with oestrus detected by progesterone measurement (Mottram, 2015). The scale of such studies means that the number of comparisons per published paper is generally limited to one or two test systems and the chosen control. The first systems for recording automatic oestrus behaviour occurred in the 1980s (Mottram, 2015). Since the advent of robotic and high-throughput milking, new automated technologies have been applied to improve monitoring of fertility (Mottram, 2015). Some of the detection systems have been commercialised and are widely adopted, whilst others remain in the research laboratory. Commercialised methods vary in their precision, level of automation and cost (capital and consumable) but all can be used to supplement visual observation. Oestrus and Biological Signals Peters and Ball (1995) described the sequence of events associated with the ovarian cycle in dairy cows. For the purposes of detection of the stage of the ovarian cycle, 50 International Animal Health Journal

Fig.1 Movement collars have been widely invested in, to monitor increased movement associated with oestrus

the cow may emit a number of hormonal and behavioural signals which may be utilised as external measurements for detecting oestrus (Mottram, 2015). Schofield (1988) showed that in relation to behavioural signals, standing to be mounted was not a reliable indicator of a cow being suitable to be served, with as many as 21% of ridden cows being already pregnant. This behaviour is due to waves of oestrogen occurring at intervals during pregnancy and may result in cows being re-inseminated and an incorrect date of the AI that resulted in pregnancy being recorded (Ball, personal communication). Back and others (2014), using daily observation of seven behaviours associated with oestrus in a once-a-day milked system, demonstrated that a scoring system that totalled either the number of behaviours exhibited or the number exhibited multiplied by the number of times exhibited in a period of time, could be successfully used to detect oestrus. Detection Devices Whilst a large number of signals have been identified, the development and conversion of detector systems from the research to commercialised systems is smaller. Commercialised systems are summarised in Table 1. Volume 4 Issue 3


LIVESTOCK Method

Automated

Manual

Mount detectors

An electronic, radiotelemetric, pressure sensitive, rump mounted device has been reported on (Steveson et al 1996). Similarly, Hempstalk et al (2013) reported on a dye patch system using a camera system to automatically measure whether the heat patch has been triggered.

A dye patch system is available relying on visual detection e.g. Kamar, Estrotect. Tail paint markers are also available.

Movement detectors: pedometers

There are electronic devices strapped to cows’ legs to count steps. Counts per cow are compared to baseline count which would be expected from the cow if it were not expecting oestrus (Mottram 2015). Peter and Bosu (1986) tested the device and found 76% of ovulations were detected compared with 35% by herdsman observations. Koelsch et al (1994) tested the device using milk progesterone level as the reference. The device demonstrated high specificity (99%) but at the cost of sensitivity (69%). Mottram (2015) concluded that pedometers were not capable of providing completely reliable ovulation detection. Van Vliet and Van Eerdenburg (1996) investigated pedometers further and the conclusion was that step counting was not reliable as an indicator of ovulation as about 20% of cows do not exhibit set behaviours.

Movement detectors: collars

Collars for detecting oestrus have been available since the early 1980s but it was not until the 1990s when the integrated circuits with tri-axial accelerometers became available along with digital signal processor chips that collars have become an alternative option – especially with the advent of cheap tri-axial accelerators and digital signal chips (Mottram 2015).The Voronin et al (2011)invention provided a method and device for detecting oestrus in animals by sensing over time the motion of the animal and identifying when the sensed motion is not related to eating periods of the animal. Kamphuis et al (2012) had similar results to those of pedometers with relatively low sensitivity but high specificity.

Milk progesterone assay

A biosensor system consists of a sensor, a system to interrogate it and a microcomputer to convert the electrical signal into a format to be displayed to an operator or computer program. The sensing methods are usually based on a monoclonal antibody, which is specific to the compound being detected. A review of systems suitable for agricultural applications was conducted by VelascoGarcia and Mottram (2003). Such systems are available integrated within some robotic and parlour milking facilities eg Herd Navigator.

A lateral flow dipstick has been developed (P4 Rapid) to provide qualitative evaluation of the P4 levels in milk.

Table 1: Summary of the main commercialised automated and manual heat detection systems, excluding behavioural observation

The increase in milk temperature, as a surrogate for the cow’s temperature that is associated with oestrus, has been investigated but the results (sensitivity of approximately 40% and 70% false positives) were considered unreliable (MacArthur et al., 1992). In relation to thermal infrared scanning of the body surfaces of a cow to detect temperature changes, Hurnik et al. (1985) concluded that high frequency of false positives and false negatives meant that the technique was not suitable for routine oestrus detection. Future Dairy (2012) investigated the technique further. Milk yield shows a pattern, although this has not proved sufficiently specific to pinpoint oestrus; however, within mixed monitoring systems it may provide an input. Pheromonal odours associated with oestrus have been the subject of research. Odours may be distributed throughout the body (Kiddy et al., 1984). Whilst those secreted from the perineal glands near the vagina may be the main attractants for the bull (Blazquez et al., 1988), Llobet et al. (1999) indicated that an array of tin oxide sensors could discriminate between oestrus and di-oestrus from the odour of vaginal swabs but not from air samples taken from the surface of the cow. A subsequent study did not produce encouraging results (Mottram et al., 2000). www.animalhealthmedia.com

Various studies (Maatje et al., 1997; Mitchell et al., 1996), using a combination of multivariate oestrus detection factors, have indicated potential in relation to % sensitivity and % false positive rates; however, further research appears to be warranted (Mottram, 2015). Progesterone Measurement Milk or blood progesterone (P4) level gives a reliable indicator of ovulation with progesterone levels elevated in cows from 4–16 days post-ovulation, then falling to a nadir (Mottram, 2015). The hormone oestradiol has an inverse relationship to progesterone, so that as progesterone levels fall, those of oestradiol rise. The oestradiol stimulates the oestrus behaviour which is most commonly used to select cows for insemination. The optimum time to inseminate the cow is 6–12hrs after the peak in oestradiol concentration (Mottram, 2015). Thus, P4 concentration in cows’ milk is used to monitor cyclicity (Samsonova et al., 2015) and confirm oestrus behaviour, as well as to perform non-pregnancy diagnosis on days 19-21 after insemination (Posthuma-Trumie et al., 2009). Milk is a convenient medium of sample collection because probes are readily available and, moreover, International Animal Health Journal 51


LIVESTOCK P4 concentration in milk is higher than in blood and the levels are closely correlated (Laing and Heap, 1971; Dobson et al., 1975). Milk P4 test is the earliest proven method of identification of non-pregnant cows with high sensitivity (Eddy and Clark, 1987). Nebel (1988) reviewed the development of the immunesensing tests for progesterone. McLeod and Williams (1991) showed that 99% of 88 ovulations were correctly identified using on-farm progesterone kits, compared with 78% in a control group monitored conventionally. Esslemont (1993) reported ovulation detection rates of 98% using progesterone assay. Biosensors for progesterone in automated systems encompass a series of different devices, the objectives of which are to identify specific complex biological molecules by a change in electrical or opto-electronic signal (Mottram, 2015). A biosensor system consists of a sensor, a system to interrogate it and a microcomputer to convert the electrical signal into a format to be displayed to an operator or computer program. The sensing methods are usually based on a monoclonal antibody, which is specific to the compound being detected. A review of systems suitable for agricultural applications was conducted by VelascoGarcia and Mottram (2003). Such systems are available and are integrated within some robotic and parlour milking facilities. To develop a lateral flow immunoassay in whole cowâ&#x20AC;&#x2122;s milk, a few aspects need to be addressed. The assay should detect P4 in the required concentration range (1-10ng/mL) and should be applicable to such a complicated matrix as undiluted milk (Samsonova et al., 2015). Waldmann and Raud (2016) compared the Ridgeway Research Limited lateral flow device (P4 Rapid) with the enzyme immunoassay commercial test and found that P4 Rapid could be used reliably to evaluate milk P4 level on the day of AI, so as to confirm signs of oestrus. They also concluded that P4 Rapid could also be used for nonpregnancy diagnosis on day 24 after AI. Ingenhoff et al. (2016), in assessing the diagnostic sensitivity and specificity of P4 Rapid for detecting a corpus luteum, concluded that the strategic use of the product can improve herd reproductive performance by facilitating decisions on whether to rebreed cows previously diagnosed as pregnant. Cost-benefit Considerations of Commercialised Systems The cost of oestrus detection methods varies considerably, with automated systems generally requiring capital outlay, whilst the cost of non-automated systems tends to consist of consumable items. The cost benefit is simplistically the value of a semen straw saved, but a broader economic consideration would include the cost of days open saved through improved heat detection and the saved cost of culling. However, the values to be attributed to each of these savings will vary according to current input and output costs and so the calculation is not trivial (Bewley et al., 2010). Alongside this, the cost of labour to implement and manage the system must be considered. The positive impacts of increased oestrus detection rates are: improved insemination results, controlled calving interval and total pregnancy rate (Stumpenhausen, 2001). Undetected and falsely detected oestrus result in missed and untimely inseminations with consequent losses of 52 International Animal Health Journal

income due to unexploited potential of milk and calf production (Firk et al., 2002). The accuracy of a method of oestrus detection can be described in terms of its sensitivity and positive predictive value (PPV). For example, the sensitivity of an activity oestrus detection system was 89.2% when tested on a commercial New Zealand farm and its PPV was 83.3%. The PPV value increased to 99.4% when tail paint and cow history were added, illustrating how several methods may contribute to the overall result (Rue et al., 2014). Discussion There are a wide variety of oestrus detection methods that have been commercialised. Whatever system is chosen for a farm, it must work for the herdspeople and cows such that it can be integrated into management systems costeffectively, and involve the least possible time that cows are away from their lying or feeding areas. Good heat detection is an intrinsic part of successful AI, permitting insemination at the optimal time of oestrus, and thereby maximising production parameters such as services per conception and calving interval. Conclusion Real time oestrus detection systems have developed significantly since the 1980s, in a farm support industry that is still evolving. It is anticipated that further innovation will deliver better results and returns for the dairy farmer and improved cow welfare by reducing culling and fertility interventions. Importantly, commercially available methods are on the farm, permitting real-time fertility management. Conflict of Interest Maggie Fisher is Director of Ridgeway Research Limited. REFERENCES 1. Back, P.J. et al, 20014. Validation of a visual oestrus scoring system for use in diary herds. Abstract. 2. Bewley, J.M., Boehlje, M.D., Gray, A.W., Hogeveen, H., Kenyon, S.J., Eicher, S.D., Schultz, M.M. (2010) Stochastic simulation using @Risk for dairy business investment decisions. Agricultural Finance Review 70: 97-125 3. Blazquez, N.B., French, J.M., Long, S.E., Perry, G.C. (1988) A pheromonal function for perineal skin glands in the cow. Veterinary Record 123: 49-50 4. Boyd, H. (1992) Estrus and estrous cycles: problems and failures. In Bovine medicine. Ed. A.H. Andrews., R.W. Blowey., H. Boyd., E.G. Eddy. Oxford, Blackwell Science. pp 433-448 5. Claus, R., Karg, H., Zwiauer, D., von Butler, I., Pirchner, F., Rattenberger, E. (1983) Analysis of factors influencing reproductive performance of the dairy cow by progesterone assay in milk-fat. British Veterinary Journal 139: 29-37 6. Dobson, H., Midmer, S.E., Fitzpatrick, R.J. (1975) Veterinary Record 96 222-223 7. Eddy, R.G., and Clark, P.J., 1987. Oestrus detection in dairy cows using an ELISA progesterone test. Vet. Rec. 120 31-4 8. Esslemont, R.J. (1973) Oestrus behaviour in dairy cows. The Veterinary Record 93 252 - 253 9. Esslemont, R.J. (1993) Relationship between herd calving to conception interval and culling rate for failure to conceive. Vet Rec. 133 163-4. 10. Firk, R., Stamer, E., Junge, W., Krieter, J. (2002) Automation Volume 4 Issue 3


Teaming up for animal health

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TESTING RvA L 120

International Animal Health Journal 53


LIVESTOCK of oestrus detection in dairy cows: a review. Livestock Production Science 75 219 – 232 11. Foulkes, J.A., Cookson, A.D., Sauer M.J. (1982) AI in cattle based on daily microtitre plate enzymeimmunoassay of progesterone in whole milk. British Veterinary Journal 138 515 12. Future Dairy (2012) Heat detection research. http:// adf.farmonline.com.au/news/magazine/equipmentand-technology/technology/heat-detectionresearch/2639984.aspx. Accessed March 15, 2015 13. González-Recio, O., Pérez-Cabal, M.A., Alenda, R. (2004) Economic value of female fertility and its relationship with profit in Spanish dairy cattle. J. Dairy Science 87 3053 - 3061 14. Hempstalk, K., Burke, C.R., Kamphius, C. (2013) Verification of an automated camera-based system of oestrus detection in dairy cows. Proceedings of the New Zealand Society of Animal Production 73: 26-28 15. Hurnik, J.F., Webster, A.B., DeBoer, S. (1985) An investigation of skin temperature differentials in relation to estrus in dairy cattle using a thermal infrared scanning technique. Journal of Animal Science 61: 1095-1102 16. Ingenhoff, L., Hall, E., House, J.K. (2016) Evaluation of a cow-side milk progesterone assay and assessment of the positive predictive value of oestrus diagnosis by dairy farmers in New South Wales. Australian Veterinary Journal 94 445 - 451 17. Kamphius, C., DelaRue, B., Burke, C.R., Jago, J. (2012) Field evaluation of 2 collar-mounted activity meters for detecting cows in estrus on a large pasture-grazed dairy farm. Journal of Dairy Science 95: 3045-3056 18. Kiddy, C.A., Mitchell, D.S., Hawk, H.W. (1984) Estrusrelated odors in body fluids of dairy cows. Journal of Dairy Science 67: 388-391 19. Koelsch, R.K., Anaeshansley, D.J., Butler, W.R. (1994) Analysis of activity measurement for accurate estrus detection in dairy-cattle. Journal of Agricultural Engineering Research 58: 107-114 20. Laing, J.A., Heap, R.B. (1971) British Veterinary Journal 127 19-22 21. Llobet, E., Hines, E.L., Gardner, J.W., Barlett, P.N., Mattram, T.F.F. (1999) Fuzzy ARTMAP based electronic nose data analysis. Sensors and Actuators B 61: 183-190 22. Lopez, H., Caraviello, D.Z., Satter, L.D., Fricke, P.M., Wiltbank, M.C. (2005) Relationship between level of milk production and multiple ovulations in lactating dairy cows. Journal of Dairy Science 88: 2783-2793 23. Maatje, K., deMol, R.M., Rossing, W. (1997) Cow status monitoring (health and estrus) using detection sensors. Computers and Electronics in Agriculture 16: 245-254 24. MacArthur, A.J., Easdon, M.P., Gregson, K. (1992) Milk temperature and detection of estrus in dairy cattle. Journal of Agricultural Engineering Research 51: 29-46 25. McLeod, B.J., Williams, M.E. (1991) Incidence of ovarian dysfunction in post partum dairy cows and the effectiveness of its clinical diagnosis and treatment. Veterinary Record 128: 121-124 26. Mee, J.F. (2007) The role of the veterinarian in bovine fertility management on modern dairy farms. Theriogenology 68S S257-S265 27. Mitchell, R.S., Sherlock, R.A., Smith, L.A. (1996) An investigation into the use of machine learning for determining estrus in cows. Computers and Electronics in Agriculture 15: 195-213 28. Mottram, T.T.F., Lark, R.M., Lane, A., Wathes, D.C., Persaud, K.C., Swan, M., Cooper, J.M. (2000) Techniques to allow 54 International Animal Health Journal

the detection of oestrus in dairy cows with an electronic nose. Electronic nose and olfaction. Proceedings of the 7th International Symposium on Olfaction and Electronic Noses, Brighton, UK 2004, pp201-208 29. Mottram, T. (2015) Animal board invited review: precision livestock farming for dairy cows with a focus on oestrus detection. Animal: 1-10 30. Nebel, R.L. (1988) On-farm milk progesterone tests. Journal of Dairy Science 71: 1682-1690 31. Peter, A.T., Bosu, W.T.K. (1986) Postpartum ovarian activity in dairy-cows – correlation between behavioural estrus, pedometer measurements and ovulations. Theriogenology 26: 111-115 32. Peters, A.R., Ball, P.J.H. (1995) Reproduction in cattle. Second edition, Blackwell Science 33. Posthuma-Trumpie, G.A., Korf, J., van Amerongen, A. (2009) Anal. Bioanal. Chem. 393 569 - 582 34. Pryce, J.E., Royal, M.D., Garnsworthy P.C., Mao, I.L. (2004). Fertility in the high-producing dairy cow. Livestock Production Science 86 125 – 135 35. Rue, B.T. d., et al (2014) Using Activity-based monitoring systems to detect dairy cows in oestrus: a field evaluation. New Zealand Veterinary Journal 62 57 - 62 36. Samsonova, J.V., Safronova, V.A., Osipov, A.P. (2015) Pretreatment-free lateral flow enzyme immunoassay for progesterone detection in whole cows’ milk. Talanta 132 685 - 689 37. Schofield, S.A., Phillips, C.J.C., Owens, A.R. (1991) Variation in the milk-production, activity rate and electricalimpedance of cervical-mucus over the estrus period of dairy cows. Animal Reproduction Science 24: 231-248 38. Steveson, J.S., Smith, M.W., Jaeger, J.R., Corah, L.R., Lefever, D.G. (1996) Detection of estrus by visual observation and radiotelemetry in peripubertal, estrus-synchronized beef heifers. Journal of Animal Science 74: 729735 39. Stumpenhausen, J. (2001) Tieraktivitätsmessung mit Pedometern zur Veresserung des Gesundheits – und Fruchtbarkeitsmanagements in Milchviehherden. In: Bau, Technik und Umwelt in der landwirtschaftlichen Nutztierhaltung, Bieträge zur 5. Internationalen Tagung in Hohenheim 6-7 März 2001. Hrsg Institut für Agrartechnik der Universität Hohenheim, Germany, pp. 272 276 40. Van Vliet, J.H., Van Erdenburg, F.J.C.M. (1996) Sexual activities and oestrus detection in lactating Holstein cows. Applied Animal Behaviour Science 50: 57-69 41. Velasco-Garcia, M.N., Mottram, T.T.F. (2003) Biosensor technology addressing agricultural problems. Biosystems Engineering 84: 1-12 42. Voronin, V., Brayer, E., Ben-Menachem, U. (2011) Method and device for detecting estrus, May 26, Patent Application No. 20110125065 43. Waldmann, A., Raud, A. (2016). Comparison of a lateral flow milk progesterone test with enzyme immunoassay as an aid for reproductive status determination in cows. Veterinary Record 10.1136/vr.103605 44. Walsh, S.W., Williams, E.J., Evans, A.C.O. (2011). A review of the causes of poor fertility in high milk producing dairy cows. Animal Reproduction Science 123 127 - 138 Acknowledgements Toby Mottram is acknowledged for his input. Georgia Parker and Peter Holdsworth are acknowledged for Figs 1 and 2 respectively. Volume 4 Issue 3


LIVESTOCK

Fig.2 Oestrus detection in dairy herds has the advantage that the cows are presented for milking normally twice-daily, which can be utilised to detect oestrus. In contrast, beef breeds are not milked and so present further challenges for oestrus detection where AI is used.

Dr Maggie Fisher She graduated in 1986 from the Royal Veterinary College and now runs three businesses (a parasitology consultancy, a CRO/laboratory and a veterinary project management facility). Dr Fisher has been active in the establishment and advancement of a number of animal health associations, including WAAVP, EVPC, AVC and ESCCAP. Email: maggie@shernacre.co.uk

Dr Peter Holdsworth He was the founding Chief Executive Officer of Animal Health Alliance (Australia) Ltd â&#x20AC;&#x201C; the peak industry body in Australia representing R,D&E companies, registrants, manufacturers and marketers of veterinary medicines, veterinary chemicals and biologics in Australia. Dr Holdsworth holds a Doctor of Philosophy in parasitology from Queensland University in Australia and is immediate past President of WAAVP. Email: pholdsworth@ridgewayresearch.co.uk

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International Animal Health Journal 55


SPECIAL FEATURE

HfA: Rabies Feature

This month, we mark another World Rabies Day – a day of action and awareness for the prevention of a disease that still kills tens of thousands of people each year. As impressive as this globally-coordinated series of activities is, we must hope that World Rabies Day is no longer needed a decade from now. The target agreed by the World Health Organization, the World Organisation for Animal Health, the UN Food and Agriculture Organization and the Global Alliance for Rabies Control (which coordinates World Rabies Day), is to reduce human deaths from canine rabies to zero by 2030. While many health professionals think of rabies as a problem of the past, the 2030 target highlights the devastating impact the disease still has in many parts of the world. Africa and Asia account for 99 per cent of human deaths from a disease that disproportionately impacts poor, rural communities.1 What’s more, one of the cruellest dimensions of rabies is its impact on the young; 40 per cent of victims are children under 15,2 and so these communities face huge emotional and economic hardship as their young people are lost to an entirely preventable disease.

But vaccination can also go with the grain of the culture, rather than against it. In Kenya, clever officials often organise vaccination drives around the school holidays. Children have the strongest relationships with the local dogs, so they are best placed to safely collect and lead them to vaccination sites. It’s a colourful, touching example of the human-animal bond, but also an eminently practical response to the inherent challenges of vaccination. And there are other positive precedents we can look to. The extraordinary reduction of canine rabies in the Latin America and the Caribbean region (LAC) was born out of a regional, political commitment made in the 1980s to control the disease. It demonstrated how campaigns can be effective when a long-term strategy that outlines clear steps towards eradication is put in place. This allowed animal medicines companies to plan ahead and ensure they could deliver vaccinations when they were urgently needed. As a result, national and subnational programmes have delivered more than 51 million doses of canine vaccine annually, along with improved diagnosis and surveillance. Together, these have resulted in a plunge from 25,000 cases of laboratory-confirmed dog rabies in 1980 to fewer than 300 in 2010.7

It’s been more than a century since Louis Pasteur and his colleagues developed a vaccine for a disease whose dramatic symptoms plagued communities and horrified the 19th century scientific community. Today, people affected by rabies are no longer fated to the suffering that characterised Pasteur’s era. Instead, victims in many parts of the world simply do not have access to the post-exposure treatments3 that can be the difference between life and death.

In each one of the WHO’s best practice examples of disease control – in The Philippines, Tanzania and Bangladesh – mass, coordinated vaccination and management was an essential driver of success.

What’s more, the problem isn’t dealt with at the source in many parts of the world. Looking purely at the economics, the cost of vaccinating dogs is minimal (as little as $0.57 per treatment in India), when compared against the US$1.7bn spent in treating people who contract rabies.

Education also has a role to play, in simple strategies like teaching children about the body language of aggressive dogs, and it’s exactly this kind of awareness that the Global Alliance for Rabies Control (GARC) hopes to foster through World Rabies Day.

Research and modelling suggest that vaccinating 70 per cent of the dog population in any given region is enough to eliminate canine rabies, regardless of the number of dogs.4

Examples across the world show that vaccines, combined with investment, patience and political will, can consign rabies to history.

Clearly, this kind of vaccination coverage represents a major logistical challenge, particularly in those parts of the world where veterinary infrastructure is lacking. Even smaller-scale programmes require considerable investment and patience from public and private sectors before results are achieved.5

So there is hope for all of us that you won’t be reading about World Rabies Day 20 years from now.

These programmes all shared a sense of scale, operating over multiple territories, along with a coordinated network of professionals and sustained investment and effort over the course of years.

The task of eradication may be made more complex by the unique cultural environment. In Bali, for instance, the population may be reluctant to reduce the free-roaming tendencies of its dogs, who serve an important cultural purpose as the protectors of property.6 56 International Animal Health Journal

Volume 4 Issue 3


SPECIAL FEATURE

A case study in rabies control: lessons learnt in the Philippines8 An ambitious, WHO-coordinated pilot programme in The Philippines aimed to halve the number of all rabies cases – both human and animal by 2016. Mass dog vaccination was identified as the most cost-effective means of preventing and reducing the transmission of rabies. The programme also included a central database system that allowed data on human health and animal health to be seen together in a One Health approach. The decrease in the number of positive canine rabies cases between 2008 and 2013 more than halved in one region and dropped from 108 to just three in another. The importance of a strong legal framework, data management, logistics and facilities were all emphasised in the learnings from the programme. Key stats9 • 197 human rabies deaths per year • 23.70% dog vaccination coverage • $78,176,489 USD cost of rabies to the Philippines economy each year* • 242,725 post-exposure treatments per year * Economic costs due to productivity losses from premature deaths, direct expenditure on PEP and lost income whilst seeking PEP10

A case study in rabies control: lessons learnt in Bangladesh11 In 2010, 2000 humans died from rabies. In response, Bangladesh launched a canine rabies elimination programme to reduce human deaths and seek to eliminate the disease. The country adopted a national strategic plan for the elimination of rabies by 2020 and to reduce human deaths by 90% by 2015. Mass dog vaccination was initiated in 2011 in combination with local capacity building and knowledge transfer, with the aim of completing three rounds of vaccination in a phased manner to interrupt the dog transmission cycle, eliminate rabies and remove the need for human rabies prophylaxis. As a result of these concerted efforts, rabies deaths decreased by around 50% between 2010 and 2013. There was also an increased availability of free vaccines and rabies immunoglobulin at centres in all 64 districts of the country. Key stats12 • 933 human deaths each year • 5.09% dog vaccination coverage • $74,259,909 USD cost of rabies to Bangladesh economy each year • 92,585 post-exposure treatments per year * Total costs were mainly due to productivity losses from premature deaths, direct expenditure on PEP, and lost income whilst seeking PEP13

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International Animal Health Journal 57


SPECIAL FEATURE

A case study in rabies control: Lessons learnt in South America14 In the Americas, human rabies transmitted by dogs is in the process of being eliminated. Since the launch in 1983 of a regional programme for the elimination of rabies transmitted by dogs, there has been a 95% reduction in the number of human cases and 98% in dogs in the Americas to date. This success has been achieved mainly through the implementation of effective policies and programmes that focus on regionally coordinated dog vaccination campaigns, raising public awareness, and widespread availability of post-exposure treatments. These activities have resulted in a plunge from 25,000 cases of laboratory-confirmed dog rabies in 1980 to fewer than 300 in 2010.

Animal Health Matters Animal Health Matters is a new website based on a joint collaboration between the World Veterinary Association (WVA) and HealthforAnimals. The resource seeks to educate and build greater awareness of the most pressing issues in human and animal health, including the threat of zoonotic diseases like rabies, and the actions being taken to tackle them, antimicrobial resistance, global food security and the future role and health of companion animals. REFERENCES 1. (Knobel DL et al., 2005; WHO, 2013a; Hampson K et al., 2015; Sambo M et al., 2013). 2. OIE, WHO and Food and Agriculture Organization of the United Nations (2015) Rabies: rationale for investing in the global elimination of dog-mediated human rabies. 3. (Knobel DL et al., 2005; WHO, 2013a; Hampson K et al., 2015; Sambo M et al., 2013). 4. OIE, WHO and Food and Agriculture Organization of the 58 International Animal Health Journal

United Nations (2015) Rabies: rationale for investing in the global elimination of dog-mediated human rabies. 5. Townsend SE et al., 2013 6. http://bawabali.com/bali-heritage-dog/2585-2/ 7. Vigilato MAN, Clavijo A, Knobl T et al. Progress towards eliminating canine rabies: policies and perspectives from Latin America and the Caribbean. Philosophical Transactions of the Royal Society B: Biological Sciences. 2013;368(1623):20120143. doi:10.1098/rstb.2012.0143. 8. OIE, WHO and Food and Agriculture Organization of the United Nations (2015) Rabies: rationale for investing in the global elimination of dog-mediated human rabies 9. Estimating the Global Burden of Endemic Canine Rabies, K. Hampson et al. PloS Negl Trop Dis. 20015;9(5) 10. Estimating the Global Burden of Endemic Canine Rabies, K. Hampson et al. PloS Negl Trop Dis. 2015 May;9 (5) 11. OIE, WHO and Food and Agriculture Organization of the United Nations (2015) Rabies: rationale for investing in the global elimination of dog-mediated human rabies 12. Estimating the Global Burden of Endemic Canine Rabies, K. Hampson et al. PloS Negl Trop Dis. 20015;9(5) 13. Estimating the Global Burden of Endemic Canine Rabies, K. Hampson et al. PloS Negl Trop Dis. 2015 May;9 (5) 14. WHO Epidemiology and Burden of disease, http://www. who.int/rabies/epidemiology/en/

Carel du Marchie Sarvaas Executive Director, HealthforAnimals and Former Director for Agricultural Biotechnology at EuropaBio. Mr Carel Du Marchie Sarvaas, a Dutch national, has many years of experience as a senior public affairs and communications advisor in Brussels, The Hague, and Washington DC. He has broad knowledge of the key issues facing the industry with extensive experience of designing and implementing integrated public affairs and communication strategies. Email: cdmsarvaas@ifahsec.org

Volume 4 Issue 3


We care for companions. We love our pets and try to keep them healthy. But they can be at risk of fleas, ticks and mosquitoes. These parasites can carry dangerous diseases. Bayer Animal Health supports animal owners and veterinarians in the prevention and treatment of parasites.

www.cvbd.org

@Bayer4Animals www.animalhealthmedia.com

International Animal Health Journal 59


SPECIAL FEATURE

UK Pet Population and Pet Food Market

The Pet Food Manufacturers’ Association (PFMA) is the principal trade body representing the UK pet food industry. Since 2008, PFMA has been tracking the UK pet population working with TNS, a globally recognised leader in consumer research, to provide robust data. This data is used by PFMA members and a wide range of bodies including government departments, pet care businesses, welfare charities and the media. The data provides interesting facts and figures about all pet types – but it is also used to shape strategies and as such, the quality and accuracy of this data is therefore critical.

To ensure a robust set of results, TNS gather the data through an omnibus survey with a sufficiently large sample. The data is averaged across two years, which gives a sample size of approximately 8000 households. These figures are considered by industry standards to be very strong, with a confidence interval of 95% and 1% margin of error. Here is a Snapshot of How the UK Pet Population is Faring: • The UK has a pet population of approximately 54 million • 12 million (44 per cent) households have at least one pet • Around 33 million pets are aquatic; 21 million are nonaquatic • Over a third of households with children said they would consider a small mammal as a pet • Just over half of the households surveyed state that dogs are the perfect pets • Over a third of cat-owning households have two or more cats Cats Claw Their Way Into the Affections of Men The new research confirmed a 500,000 rise in the cat population. This increase is largely driven by a rise of over 25 per cent in the number of men owning cats, which has now reached eight million. More young people are also choosing to keep cats, with those aged 16–34 up three per cent and those aged 35–44 increasing two percent. First

60 International Animal Health Journal

Volume 4 Issue 3


SPECIAL FEATURE First Pets As with general ownership patterns, cats were more likely to have been a first pet in the south-east and dogs in the north. Rabbits, hamsters and guinea pigs made up a total of 10% (5%, 4% and 1% respectively). This is, in relative terms, a lot higher than the proportions of those species in the general population survey, suggesting that small animals are more likely to be owned by households with children as ‘first pets’. Of the 2124 households asked, 28% said that they had or would consider owning a small mammal; 35% of households with children reported that they would consider a small mammal.

• 90% of vets agree that prepared pet food provides optimum nutrition when fed correctly (LVS November 2016)

Michael Bellingham, PFMA Chief Executive, comments: “Some people assume it is difficult to look after a small mammal and they don’t know how to provide the right care. There is a wealth of educational resources out there to support would-be owners so they don’t need to miss out. However, it is important that people do the research first to make sure they are choosing a pet appropriate to their lifestyle and that they can provide the right care. Information is available from welfare charities and organisations such as PDSA and RSPCA and as the experts in nutrition, PFMA provides feeding factsheets and guidance. In the survey, the perfect pets were given as dogs (53%) and cats (23%). The two reasons given for nominating a perfect pet were companionship (39%) and ease of looking after (28%). Variations in these two responses came with the age of the respondents with predictable results… an older person was more likely to report the reason as companionship; a younger person for ease of looking after (although the variations are not huge). Nutrition – Reading the Facts As PFMA is all about nutrition, we also surveyed the public to garner insights on feeding behaviour.

Where Do UK Pet Owners Acquire their Feeding Knowledge?

• Our research shows that 88% of owners choose a commercially prepared pet food but we know that owners supplement with snacks. Our Obesity Report (2014) confirmed that over a third of owners use ‘human’ food to treat. 53% of dog owners who feed table scraps do so daily and 49% of cat owners who feed table scraps do so daily. • In terms of attitudes towards reading nutritional information on the pet food label, 43% of owners never read this, and the main reason (40%) is that they never read information on packaging. A further 9% claim no interest in calorie consumption by their pet(s). 35% claim to already have the relevant knowledge about the correct diet for their pet(s). However, feeding guidelines are a vital piece of information on the pet food label as they provide recommended portion sizes based on the size/weight of a pet. PFMA advises owners to follow the feeding guidelines, adapting to the individual needs of their pet. • According to a survey of the veterinary profession conducted at the London Vet Show (November 2016), vets believe that 49% of dogs, 44% of cats, 32% of small mammals and 11% of birds are overweight or obese.

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Market Growth The pet food market saw growth in value in 2016 and has now reached £2.6 billion (excluding wild bird). Volume growth was flat, in line with the pet population, as expected in a mature market. PET

VOLUME 000 TONNES

VALUE £M

Dog

835

1348

Cat

406

1108

Fish

3

69

Small animals

69

68

Pet bird

12

12

Total pet

1325

2605

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SPECIAL FEATURE

Delving into More Detail, Key Highlights from the PFMA Market Data Report Include: • The most dynamic areas of growth in both the cat and dog food markets have been in specialist, niche products, including those focusing on specific health attributes • In dog food, the strongest growth has been seen at the premium end of the market, in line with 2015 • In 2015, PFMA members reported that the strongest growth areas in the cat food market had been at the premium and value ends of the market; however, in 2016 the spread is more even • Dry complete dog food is the dominant feed for UK dogs, accounting for 50% of total volume. This sector is now estimated to be worth £573m • Dry complete cat food was the fastest growing of the main meal categories for cats in recent years • The cat treat market has been showing dramatic growth for many years. Currently valued at £126m, the market is now worth six times the amount it was worth in 2007 • The small animal market fell in 2016 which may reflect the broader trend of a decline in pet ownership in the UK Michael Bellingham, PFMA Chief Executive, summarises how the market is performing: “The pet food market saw growth of 2% in 2016 with the market continuing to an alltime high of £2.6 billion. Without doubt the field of pet nutrition moves at a fast pace. The offering has changed dramatically over the years, moving us from basic pet foods that provide the right nutrients in the right quantities to more sophisticated foods that do this and more. In terms of trends, humanisation of pets continues to be the biggest and most impactful trend in the pet food industry.” 62 International Animal Health Journal

Wild Birds and Feeding Habits PFMA also represents manufacturers of wild bird feed. Feeding the birds is a good way for people of all ages to connect with nature and can also provide a source of companionship. Key findings in our survey are: • Amongst the 93% of households with some form of outdoor space, 43% of households feed wild birds • Older householders are more likely to feed wild birds, as are those who also have pet birds. Younger households (with children) are less likely to feed wild birds • The time of year most associated with the feeding of wild birds is winter, when 51% say they feed over this season. This proportion grows in rural areas (to 57%) and this is an ongoing theme, as rural dwellers are more likely to feed the birds than their urban counterparts

Nicole Paley PFMA Communications Manager and runs the PFMA Press Office. Nicole also sits on the Communications Working Group of the European Pet Food Federation, FEDIAF and participates in the communications discussions of the Global Pet Food Alliance, GAPFA. Email: nicole@pfma.org.uk

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International Animal Health Journal 63


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I hope this journal guides you progressively, through the maze of activities and changes taking place in the animal health industry.

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