Animal research: toxicity testing

These studies challenge the historical assumption that animals provide predictive test models for human toxicity testing, which has provided the justification for their widespread use for this purpose. 

Animal carcinogenicity testing

Animal carcinogenicity studies: 1. poor human predictivity

Abstract

The regulation of human exposure to potentially carcinogenic chemicals constitutes society’s most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency’s (EPA’s) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or animal data also assessed by the World Health Organisation’s International Agency for Research on Cancer (IARC), human carcinogenicity classifications were compatible with EPA classifications only for those 17 having at least limited human data (p = 0.5896). For those 111 primarily reliant on animal data, the EPA was much more likely than the IARC to assign carcinogenicity classifications indicative of greater human risk (p < 0.0001). The IARC is a leading international authority on carcinogenicity assessments, and its significantly different human carcinogenicity classifications of identical chemicals indicate that: 1) in the absence of significant human data, the EPA is over-reliant on animal carcinogenicity data; 2) as a result, the EPA tends to over-predict carcinogenic risk; and 3) the true predictivity for human carcinogenicity of animal data is even poorer than is indicated by EPA figures alone. The EPA policy of erroneously assuming that tumours in animals are indicative of human carcinogenicity is implicated as a primary cause of these errors. 

Knight A, Bailey J, and Balcombe J (2006). Animal carcinogenicity studies: 1. poor human predictivity. Altern Lab Anim, 34(1), 19-27.

Animal carcinogenicity studies: 2. obstacles to extrapolation of data to humans

Abstract

Due to limited human exposure data, risk classification and the consequent regulation of exposure to potential carcinogens has conventionally relied mainly upon animal tests. However, several investigations have revealed animal carcinogenicity data to be lacking in human predictivity. To investigate the reasons for this, we surveyed 160 chemicals possessing animal but not human exposure data within the US Environmental Protection Agency chemicals database, but which had received human carcinogenicity assessments by 1 January 2004. We discovered the use of a wide variety of species, with rodents predominating, and of a wide variety of routes of administration, and that there were effects on a particularly wide variety of organ systems. The likely causes of the poor human predictivity of rodent carcinogenicity bioassays include: 1) the profound discordance of bioassay results between rodent species, strains and genders, and further, between rodents and human beings; 2) the variable, yet substantial, stresses caused by handling and restraint, and the stressful routes of administration common to carcinogenicity bioassays, and their effects on hormonal regulation, immune status and predisposition to carcinogenesis; 3) differences in rates of absorption and transport mechanisms between test routes of administration and other important human routes of exposure; 4) the considerable variability of organ systems in response to carcinogenic insults, both between and within species; and 5) the predisposition of chronic high dose bioassays toward false positive results, due to the overwhelming of physiological defences, and the unnatural elevation of cell division rates during ad libitum feeding studies. Such factors render profoundly difficult any attempts to accurately extrapolate human carcinogenic hazards from animal data. 

Knight A, Bailey J, and Balcombe J (2006). Animal carcinogenicity studies: 2. obstacles to extrapolation of data to humans. Altern Lab Anim, 34(1), 29-38.

Animal carcinogenicity studies: 3. alternatives to the bioassay

Abstract

Conventional animal carcinogenicity tests take around three years to design, conduct and interpret. Consequently, only a tiny fraction of the thousands of industrial chemicals currently in use have been tested for carcinogenicity. Despite the costs of hundreds of millions of dollars and millions of skilled personnel hours, as well as millions of animal lives, several investigations have revealed that animal carcinogenicity data lack human specificity (i.e. the ability to identify human non-carcinogens), which severely limits the human predictivity of the bioassay. This is due to the scientific inadequacies of many carcinogenicity bioassays, and numerous serious biological obstacles, which render profoundly difficult any attempts to accurately extrapolate animal data in order to predict carcinogenic hazards to humans. Proposed modifications to the conventional bioassays have included the elimination of mice as a second species, and the use of genetically-altered or neonatal mice, decreased study durations, initiation–promotion models, the greater incorporation of toxicokinetic and toxicodynamic assessments, structure-activity relationship (computerised) systems, in vitro assays, cDNA microarrays for detecting changes in gene expression, limited human clinical trials, and epidemiological research. The potential advantages of nonanimal assays when compared to bioassays include the superior human specificity of the results, substantially reduced time-frames, and greatly reduced demands on financial, personnel and animal resources. Inexplicably, however, the regulatory agencies have been frustratingly slow to adopt alternative protocols. In order to decrease the enormous cost of cancer to society, a substantial redirection of resources away from excessively slow and resource-intensive rodent bioassays, into the further development and implementation of non-animal assays, is both strongly justified and urgently required.

Knight A, Bailey J, and Balcombe J (2006). Animal carcinogenicity studies: 3. alternatives to the bioassay. Altern Lab Anim, 34(1), 39-48.

Summaries: animal carcinogenicity testing

Animal carcinogenicity studies: implications for the REACH system

This study received an award at the 13th Congress on Alternatives to Animal Testing, Linz, Austria, 2006 (the premier European conference in the field).

Knight A, Bailey J and Balcombe J (2006). Animal carcinogenicity studies: implications for the REACH system. Altern Lab Anim, 34(Suppl 1), 139-147.

Which drugs cause cancer? Animal tests yield misleading results

Knight A, Bailey J and Balcombe J (2005). Which drugs cause cancer? Animal tests yield misleading results. BMJ USA, 331, E389-E391.

Animal teratogenicity testing

The future of teratology research is in vitro

Abstract

Birth defects induced by maternal exposure to exogenous agents during pregnancy are preventable, if the agents themselves can be identified and avoided. Billions of dollars and man-hours have been dedicated to animal-based discovery and characterisation methods over decades. We show here, via a comprehensive systematic review and analysis of this data, that these methods constitute questionable science and pose a hazard to humans. Mean positive and negative predictivities barely exceed 50%; discordance among the species used is substantial; reliable extrapolation from animal data to humans is impossible, and virtually all known human teratogens have so far been identified in spite of, rather than because of, animal-based methods. Despite strict validation criteria that animal-based teratology studies would fail to meet, three in vitro alternatives have done so. The embryonic stem-cell test (EST) is the best of these. We argue that the poor performance of animal based teratology alone warrants its cessation; it ought to be replaced by the easier, cheaper and more repeatable EST, and resources made available to improve this and other tests even further.

Bailey J, Knight A and Balcombe J (2005). The future of teratology research is in vitro. Biog Amines, 19(2), 97-146.

Summary: animal toxicity testing

Animal experiments harm human health

Knight A, Bailey J, Balcombe J. Animal experiments harm human health. Amer Chronicle 2005, 8 Oct.