Downloaded from http://veterinaryrecord.bmj.com/ on January 16, 2015 - Published by group.bmj.com
Viewpoint
Viewpoint
Does exposure to thyroxine-mimics cause feline thyroid hyperplasia? Over the past four decades, the incidence of feline thyroid hyperplasia (FTH) has steadily increased. Concomitantly, cats’ exposure to thyroxine (T4)-mimicking environmental contaminants and food additives has also increased. Kate Hill and Ian Shaw hypothesise that the two could be linked. Hyperthyroidism in cats was first discovered in the late 1970s (Holzworth and others 1980). Since then, its incidence has increased from one in 1000 cats seen by veterinarians (between 1978 and 1982) to 21 in 1000 (between 1993 and 1997) (Edinboro and others 2004). Hyperthyroidism is now recognised as the most commonly diagnosed endocrinopathy in small animal practice. To understand why feline hyperthyroidism ostensibly began in 1979 and has steadily increased in incidence, we should explore the possible causes (ie, risk factors) and whether cats began to be exposed to these risk factors in 1979 and whether they have been increasingly exposed since. Despite the disease being well described there remains little insight into its causal mechanism; however, Peterson (2012) initiated a key debate on the importance of exposure to chemicals with thyroid mimicking properties as important risk factors in FTH. Here, we will expand on this thinking. Benign, functional, adenomatous hyperplasia accounts for more than 98 per cent of cats with hyperthyroidism with the majority (more than 70 per cent) having both thyroid lobes affected.
Kate Hill is a senior lecturer in small animal medicine at Massey University, New Zealand. Ian Shaw is professor of toxicology at the University of Canterbury, New Zealand. They are working on a research project exploring molecular mimicry in biological systems. K. E. Hill, Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Private Bag 11-222, Palmerston North, New Zealand 4442 e-mail: [email protected] I. C. Shaw, Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand 8140 e-mail: [email protected] 228 | Veterinary Record | September 6, 2014
Thyroid carcinomas are implicated in 2 to 3 per cent of cases. The stimuli for unscheduled cell division leading to hyperplasia or neoplasia are the subject of much debate, but it is accepted that they can be either genetic or environmental. In addition, the link, if any, between hyperplasia and neoplasia is the subject of considerable disagreement. Cell division stimuli can be preprogrammed (ie, genetic) or idiosyncratic (eg, environmental chemicals). The latter class comprises a vast array of chemicals with multifarious mechanisms of action, including chemicals that cause inflammation (eg, 2,4,6-trinitrobenzenesulfonic acid) or chemicals that induce cell division by mimicking endogenous cell proliferators (eg, 17β-estradiol mimics). Interestingly, physical insults that lead to local inflammation might also induce proliferation; for example, implanting plastic subcutaneously leads to hyperplasia, and sometimes neoplasia, at the points of irritation between the rough plastic edges and tissues (Brand and others 1976); this is thought to be due to cell division stimulated by inflammation caused by the foreign body. When a cell divides, its DNA replicates and is susceptible to replication errors, which might lead to unscheduled cell division in the daughter cells. Similarly, during replication, DNA is chemically exposed and at risk of chemical modification (eg, mutation) caused by exogenous (eg, environmental) chemicals. DNA is protected by highly sophisticated repair mechanisms which constantly survey and repair transcriptional errors or chemical modifications (eg, alkylation). Not all errors are repaired and thus cell division inevitably carries a risk of an unrepaired error
being promulgated, which might, in turn, lead to unscheduled division and in some cases tumorigenesis. Therefore, chemicals that induce cell division increase the risk of tumorigenesis due to errors in DNA replication being more likely during division. In addition, hyperplasia might be linked to neoplasia simply because, in hyperplasia, cells divide more frequently and thus the risk of tumorigenesis is concomitantly increased (Preston-Martin and others 1990). This possibly accounts for the 2 to 3 per cent of thyroid cancers that occur in cats with thyroid hyperplasia. As outlined above, there are a plethora of stimuli for cell division; these are the risk factors for hyperplasia. To begin to understand the causes of FTH, we should look at possible risk factors, including behavioural and/or chemical exposures. There are a number of environmental risk factors associated with FTH, including the use of cat litter, ectoparasite products, herbicides, pesticides and fertilisers, although the mechanism of action or the causal agents involved might not have been identified (Olczak and others 2005). Recent studies have focused on flame retardants, such as polybrominated diphenyl ethers (PBDEs), which were introduced into homes some 30 years ago. Interestingly, the time of introduction of fire retardants corresponds to the first cases of feline hyperthyroidism (Holzworth and others 1980).
Downloaded from http://veterinaryrecord.bmj.com/ on January 16, 2015 - Published by group.bmj.com
Viewpoint Cats that drink from puddles, sleep on the floor, eat canned food (particularly fish), are treated with anti-flea products and use cat litter are all at greater risk of FTH (Martin and others 2000, Edinboro and others 2004, Olczak and others 2005) than cats not exposed to these risk factors. These are all environmental risk factors that might be linked to exposure to cell division stimulants. Conflicting reports exist on the effect of herbicides, pesticides and fertilisers on the incidence of FTH. Some report increased risk (Olczak and others 2005), whereas others report no increased risk (Martin and others 2000). For example, one study reports that cats that drink from puddles have a five-fold increased risk of hyperthyroidism (Olczak and others 2005). The surprising link to drinking from puddles might be explained by the puddles containing thyroid cell division stimulants. Puddles on
‘The times of introduction of the chemical exposures associated with the FTH risk factors might explain why FTH appears to have become more common over the past four decades’ farms, for example, might be contaminated with pesticide run off from pesticidespraying equipment. Indeed, one of the most commonly used group of pesticides worldwide is the pyrethroids, which are metabolised in mammals and degraded in the environment to 3-(4-hydroxyphenoxy) phenol (McCarthy and others 2006), which has molecular structural analogies to T4 (Fig 1). Therefore, exposure to 3-(4-hydroxyphenoxy)phenol could affect thyroid cell proliferation. Similarly, some cat flea treatments (eg, flea collars) contain the pyrethroid cypermethrin, which also degrades to 3-(4-hydroxyphenoxy)phenol. Some canned cat foods are dyed with erythrosine, which has a structural analogy to T4 (Fig 1). Fish-based food might contain residues of hydrophobic environmental contaminants such as polychlorinated biphenyls, and they too have structural analogies with T4 (Fig 1). In addition, cat beds, including hammocks, are likely to be treated with flame retardants and some of these (eg, tetrabromobisphenol A [TBBPA]) mimic T4 (Fig 1). Preliminary studies (unpublished) in our laboratory have demonstrated TBBPA in a cat hammock fabric. From the above, it is clear that exposure to a range of potential thyroid cell division stimulants might be linked to FTH. The possible FTH risk factors outlined above are all chemicals used in the manufacture of products that cats in the high-risk group come into contact with on a daily basis. They are all relatively recent introductions to common usage. Pyrethroids
were introduced in the late 1900s, erythrosine has been used as a food colourant since at least the 1980s (now permitted for use only in non-foodproducing animal feeds and selected human foods (eg, maraschino cherries), and TBBPA has been used as a fabric flame retardant for at least 25 years. The times of introduction of the chemical exposures associated with the FTH risk factors might explain why FTH appears to have become more common over the past four decades. TBBPA flame retardant is physically dispersed in fabric polymers; this means it is prone to leaching and is therefore bioavailable. A cat with natural oil-coated fur lying on a cat bed made from TBBPA flame-retarded fabric is likely to partition the TBBPA from the fabric into its natural fur oils (TBBPA is approximately 100,000 times more soluble in fat than in water). When grooming, the cat is likely to ingest and FIG 1: Molecular structures of thyroxine, erythrosine, tetrabromobisphenol A (TBBPA), 3-(4-hydroxyphenoxy) absorb any TBBPA present phenol (the pyrethroid insecticide metabolite), and a on its fur. polychlorinated biphenyl (PCB) congener orientated to Cats have significant show their molecular analogies to T4. This also shows differences in their TBBPA/T4 superimposed to show their molecular xenobiotic detoxification analogies, exemplifying that TBBPA is a T4-mimic mechanisms compared to other mammals. In short, Edinboro, C. H., Scott-Moncrieff, J. C., they have reduced activities of some phase Janovitz, E., Thacker, H. L. & Glickman, II conjugation enzymes (eg, glucuronyl L. T. (2004) Epidemiologic study of relationships transferases and sulphotransferases) and between consumption of commercial canned food and instead utilise esoteric conjugation (eg, risk of hyperthyroidism in cats. Journal of the American Veterinary Medical Association 224, 879-886 with taurine) mechanisms to effect efficient Holzworth, J., Theran, P., Carpenter, J. xenobiotic metabolite excretion. It is L., Harpster, N. K. & Todoroff, R. J. (1980) possible that metabolism and clearance Hyperthyroidism in the cat: ten cases. Journal of the American Veterinary Medical Association 176, 345-353 of 3-(4-hydroxyphenoxy)phenol and Martin, K. M., Rossing, M. A., Ryland, L. TBBPA, both of which are sulphated M., DiGiacomo, R. F. & Freitag, W. A. (2000) or glucuronidated, is lower in cats, thus Evaluation of dietary and environmental risk factors for hyperthyroidism in cats. Journal of the American enhancing their toxicities. Veterinary Medical Association 217, 853-856 We propose that cats exposed to McCarthy, A. R., Thomson, B. M., Shaw, T4-mimicking thyroid cell division I. C. & Abell, A. D. (2006) Estrogenicity of pyrestimulants are at an increased risk of FTH throid insecticide metabolites. Journal of Environmental Monitoring 8, 197-202 and that the risk increases with the number Olczak, J., Jones, B. R., Pfeiffer, D. U., and the duration of exposures. Squires, R. A., Morris, R. S. & Markwell, This hypothesis could be tested at P. J. (2005) Multivariate analysis of risk factors for feline hyperthyroidism in New Zealand. New Zealand two levels: animal studies could be used to Veterinary Journal 53, 53-58 determine whether prolonged, repeat, low PETERSON, M. (2012) Hyperthyroidism in cats: dose exposure to T4-mimics results in thyroid what’s causing the epidemic of thyroid disease and hyperplasia; and epidemiological studies can we prevent it? Journal of Feline Medicine and Surgery 14, 804-818 could be used to determine whether cats with Preston-Martin, S., Pike, M. C., Ross, R. hyperthyroidism have greater exposure to K., Jones, P. A. & Henderson, B. E. (1990) T4-mimics than age/sex matched controls. Increased cell division as a cause of human cancer.
References
Brand, K. G., Johnson, K. H., Buoen, L. C. & Golberg, L. (1976) Foreign body tumorigenesis. Critical Reviews in Toxicology 4, 353-394
Cancer Research 50, 7415-7421
doi: 10.1136/vr.g3754 September 6, 2014 | Veterinary Record | 229
Downloaded from http://veterinaryrecord.bmj.com/ on January 16, 2015 - Published by group.bmj.com
Does exposure to thyroxine-mimics cause feline thyroid hyperplasia? K. E. Hill and I. C. Shaw Veterinary Record 2014 175: 228-229
doi: 10.1136/vr.g3754 Updated information and services can be found at: http://veterinaryrecord.bmj.com/content/175/9/228
These include:
References Email alerting service
This article cites 8 articles, 2 of which you can access for free at: http://veterinaryrecord.bmj.com/content/175/9/228#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Viewpoint
Viewpoint
Does exposure to thyroxine-mimics cause feline thyroid hyperplasia? Over the past four decades, the incidence of feline thyroid hyperplasia (FTH) has steadily increased. Concomitantly, cats’ exposure to thyroxine (T4)-mimicking environmental contaminants and food additives has also increased. Kate Hill and Ian Shaw hypothesise that the two could be linked. Hyperthyroidism in cats was first discovered in the late 1970s (Holzworth and others 1980). Since then, its incidence has increased from one in 1000 cats seen by veterinarians (between 1978 and 1982) to 21 in 1000 (between 1993 and 1997) (Edinboro and others 2004). Hyperthyroidism is now recognised as the most commonly diagnosed endocrinopathy in small animal practice. To understand why feline hyperthyroidism ostensibly began in 1979 and has steadily increased in incidence, we should explore the possible causes (ie, risk factors) and whether cats began to be exposed to these risk factors in 1979 and whether they have been increasingly exposed since. Despite the disease being well described there remains little insight into its causal mechanism; however, Peterson (2012) initiated a key debate on the importance of exposure to chemicals with thyroid mimicking properties as important risk factors in FTH. Here, we will expand on this thinking. Benign, functional, adenomatous hyperplasia accounts for more than 98 per cent of cats with hyperthyroidism with the majority (more than 70 per cent) having both thyroid lobes affected.
Kate Hill is a senior lecturer in small animal medicine at Massey University, New Zealand. Ian Shaw is professor of toxicology at the University of Canterbury, New Zealand. They are working on a research project exploring molecular mimicry in biological systems. K. E. Hill, Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Private Bag 11-222, Palmerston North, New Zealand 4442 e-mail: [email protected] I. C. Shaw, Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand 8140 e-mail: [email protected] 228 | Veterinary Record | September 6, 2014
Thyroid carcinomas are implicated in 2 to 3 per cent of cases. The stimuli for unscheduled cell division leading to hyperplasia or neoplasia are the subject of much debate, but it is accepted that they can be either genetic or environmental. In addition, the link, if any, between hyperplasia and neoplasia is the subject of considerable disagreement. Cell division stimuli can be preprogrammed (ie, genetic) or idiosyncratic (eg, environmental chemicals). The latter class comprises a vast array of chemicals with multifarious mechanisms of action, including chemicals that cause inflammation (eg, 2,4,6-trinitrobenzenesulfonic acid) or chemicals that induce cell division by mimicking endogenous cell proliferators (eg, 17β-estradiol mimics). Interestingly, physical insults that lead to local inflammation might also induce proliferation; for example, implanting plastic subcutaneously leads to hyperplasia, and sometimes neoplasia, at the points of irritation between the rough plastic edges and tissues (Brand and others 1976); this is thought to be due to cell division stimulated by inflammation caused by the foreign body. When a cell divides, its DNA replicates and is susceptible to replication errors, which might lead to unscheduled cell division in the daughter cells. Similarly, during replication, DNA is chemically exposed and at risk of chemical modification (eg, mutation) caused by exogenous (eg, environmental) chemicals. DNA is protected by highly sophisticated repair mechanisms which constantly survey and repair transcriptional errors or chemical modifications (eg, alkylation). Not all errors are repaired and thus cell division inevitably carries a risk of an unrepaired error
being promulgated, which might, in turn, lead to unscheduled division and in some cases tumorigenesis. Therefore, chemicals that induce cell division increase the risk of tumorigenesis due to errors in DNA replication being more likely during division. In addition, hyperplasia might be linked to neoplasia simply because, in hyperplasia, cells divide more frequently and thus the risk of tumorigenesis is concomitantly increased (Preston-Martin and others 1990). This possibly accounts for the 2 to 3 per cent of thyroid cancers that occur in cats with thyroid hyperplasia. As outlined above, there are a plethora of stimuli for cell division; these are the risk factors for hyperplasia. To begin to understand the causes of FTH, we should look at possible risk factors, including behavioural and/or chemical exposures. There are a number of environmental risk factors associated with FTH, including the use of cat litter, ectoparasite products, herbicides, pesticides and fertilisers, although the mechanism of action or the causal agents involved might not have been identified (Olczak and others 2005). Recent studies have focused on flame retardants, such as polybrominated diphenyl ethers (PBDEs), which were introduced into homes some 30 years ago. Interestingly, the time of introduction of fire retardants corresponds to the first cases of feline hyperthyroidism (Holzworth and others 1980).
Downloaded from http://veterinaryrecord.bmj.com/ on January 16, 2015 - Published by group.bmj.com
Viewpoint Cats that drink from puddles, sleep on the floor, eat canned food (particularly fish), are treated with anti-flea products and use cat litter are all at greater risk of FTH (Martin and others 2000, Edinboro and others 2004, Olczak and others 2005) than cats not exposed to these risk factors. These are all environmental risk factors that might be linked to exposure to cell division stimulants. Conflicting reports exist on the effect of herbicides, pesticides and fertilisers on the incidence of FTH. Some report increased risk (Olczak and others 2005), whereas others report no increased risk (Martin and others 2000). For example, one study reports that cats that drink from puddles have a five-fold increased risk of hyperthyroidism (Olczak and others 2005). The surprising link to drinking from puddles might be explained by the puddles containing thyroid cell division stimulants. Puddles on
‘The times of introduction of the chemical exposures associated with the FTH risk factors might explain why FTH appears to have become more common over the past four decades’ farms, for example, might be contaminated with pesticide run off from pesticidespraying equipment. Indeed, one of the most commonly used group of pesticides worldwide is the pyrethroids, which are metabolised in mammals and degraded in the environment to 3-(4-hydroxyphenoxy) phenol (McCarthy and others 2006), which has molecular structural analogies to T4 (Fig 1). Therefore, exposure to 3-(4-hydroxyphenoxy)phenol could affect thyroid cell proliferation. Similarly, some cat flea treatments (eg, flea collars) contain the pyrethroid cypermethrin, which also degrades to 3-(4-hydroxyphenoxy)phenol. Some canned cat foods are dyed with erythrosine, which has a structural analogy to T4 (Fig 1). Fish-based food might contain residues of hydrophobic environmental contaminants such as polychlorinated biphenyls, and they too have structural analogies with T4 (Fig 1). In addition, cat beds, including hammocks, are likely to be treated with flame retardants and some of these (eg, tetrabromobisphenol A [TBBPA]) mimic T4 (Fig 1). Preliminary studies (unpublished) in our laboratory have demonstrated TBBPA in a cat hammock fabric. From the above, it is clear that exposure to a range of potential thyroid cell division stimulants might be linked to FTH. The possible FTH risk factors outlined above are all chemicals used in the manufacture of products that cats in the high-risk group come into contact with on a daily basis. They are all relatively recent introductions to common usage. Pyrethroids
were introduced in the late 1900s, erythrosine has been used as a food colourant since at least the 1980s (now permitted for use only in non-foodproducing animal feeds and selected human foods (eg, maraschino cherries), and TBBPA has been used as a fabric flame retardant for at least 25 years. The times of introduction of the chemical exposures associated with the FTH risk factors might explain why FTH appears to have become more common over the past four decades. TBBPA flame retardant is physically dispersed in fabric polymers; this means it is prone to leaching and is therefore bioavailable. A cat with natural oil-coated fur lying on a cat bed made from TBBPA flame-retarded fabric is likely to partition the TBBPA from the fabric into its natural fur oils (TBBPA is approximately 100,000 times more soluble in fat than in water). When grooming, the cat is likely to ingest and FIG 1: Molecular structures of thyroxine, erythrosine, tetrabromobisphenol A (TBBPA), 3-(4-hydroxyphenoxy) absorb any TBBPA present phenol (the pyrethroid insecticide metabolite), and a on its fur. polychlorinated biphenyl (PCB) congener orientated to Cats have significant show their molecular analogies to T4. This also shows differences in their TBBPA/T4 superimposed to show their molecular xenobiotic detoxification analogies, exemplifying that TBBPA is a T4-mimic mechanisms compared to other mammals. In short, Edinboro, C. H., Scott-Moncrieff, J. C., they have reduced activities of some phase Janovitz, E., Thacker, H. L. & Glickman, II conjugation enzymes (eg, glucuronyl L. T. (2004) Epidemiologic study of relationships transferases and sulphotransferases) and between consumption of commercial canned food and instead utilise esoteric conjugation (eg, risk of hyperthyroidism in cats. Journal of the American Veterinary Medical Association 224, 879-886 with taurine) mechanisms to effect efficient Holzworth, J., Theran, P., Carpenter, J. xenobiotic metabolite excretion. It is L., Harpster, N. K. & Todoroff, R. J. (1980) possible that metabolism and clearance Hyperthyroidism in the cat: ten cases. Journal of the American Veterinary Medical Association 176, 345-353 of 3-(4-hydroxyphenoxy)phenol and Martin, K. M., Rossing, M. A., Ryland, L. TBBPA, both of which are sulphated M., DiGiacomo, R. F. & Freitag, W. A. (2000) or glucuronidated, is lower in cats, thus Evaluation of dietary and environmental risk factors for hyperthyroidism in cats. Journal of the American enhancing their toxicities. Veterinary Medical Association 217, 853-856 We propose that cats exposed to McCarthy, A. R., Thomson, B. M., Shaw, T4-mimicking thyroid cell division I. C. & Abell, A. D. (2006) Estrogenicity of pyrestimulants are at an increased risk of FTH throid insecticide metabolites. Journal of Environmental Monitoring 8, 197-202 and that the risk increases with the number Olczak, J., Jones, B. R., Pfeiffer, D. U., and the duration of exposures. Squires, R. A., Morris, R. S. & Markwell, This hypothesis could be tested at P. J. (2005) Multivariate analysis of risk factors for feline hyperthyroidism in New Zealand. New Zealand two levels: animal studies could be used to Veterinary Journal 53, 53-58 determine whether prolonged, repeat, low PETERSON, M. (2012) Hyperthyroidism in cats: dose exposure to T4-mimics results in thyroid what’s causing the epidemic of thyroid disease and hyperplasia; and epidemiological studies can we prevent it? Journal of Feline Medicine and Surgery 14, 804-818 could be used to determine whether cats with Preston-Martin, S., Pike, M. C., Ross, R. hyperthyroidism have greater exposure to K., Jones, P. A. & Henderson, B. E. (1990) T4-mimics than age/sex matched controls. Increased cell division as a cause of human cancer.
References
Brand, K. G., Johnson, K. H., Buoen, L. C. & Golberg, L. (1976) Foreign body tumorigenesis. Critical Reviews in Toxicology 4, 353-394
Cancer Research 50, 7415-7421
doi: 10.1136/vr.g3754 September 6, 2014 | Veterinary Record | 229
Downloaded from http://veterinaryrecord.bmj.com/ on January 16, 2015 - Published by group.bmj.com
Does exposure to thyroxine-mimics cause feline thyroid hyperplasia? K. E. Hill and I. C. Shaw Veterinary Record 2014 175: 228-229
doi: 10.1136/vr.g3754 Updated information and services can be found at: http://veterinaryrecord.bmj.com/content/175/9/228
These include:
References Email alerting service
This article cites 8 articles, 2 of which you can access for free at: http://veterinaryrecord.bmj.com/content/175/9/228#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
