Commentary
Uses of ‘Good Laboratory Practices’ by regulated industry and agencies, and the safety of bisphenol A Anthony C Tweedale As the argument about the risk of the ubiquitous plastic chemical bisphenol A (BPA) continues,1 we should recall that every toxic chemical is regulated the same way: with its key safety data supplied by the manufacturer with typically millions to billions of revenue a year riding on that safety question. In fact, for many years no chemical risk assessment (RA) performed for premarketing safety testing has used any but the data supplied by the chemical’s manufacturer, for the key toxicity studies which determine a chemical’s alleged low or no observable adverse effect level (L/NOAEL) (nor have many RAs on chemicals already on the market). Hundreds of thousands of peer-reviewed, published findingsdof much higher quality than the industry’s financially conflicted datadhave been ignored. I have observed this data exclusion in hundreds of RAs. For dozens of existing chemicals, I have compared these alleged L/NOAELs of industry with the toxicity studies of independent investigators. In every case, industry’s claims of a safe dose are falsified by independent academia. Indeed, reviews always find a strong correlation of chemical industry funding with published findings of safety,2e5 while too many metastudies/critical reviews to cite have shown the same bias in the pharmaceutical industry’s studies. How did society reach such a dangerous state? About 40 years ago, a toxicity test protocol called Good Laboratory Practices (GLP) was mandated by the US Food and Drug Administration (US-FDA), after gross laboratory frauds by life science and petrochemical companies.6 GLP imposes simple record-keeping/chain-of-custody data and test animal standardisation requirements on toxicology laboratories. Yet today, only chronic toxicity tests that use GLP are allowed in almost the Correspondence to Anthony C Tweedale, R.I.S.K. Consultancy, PB 617, Brussels-1 1000, Belgium;
[email protected] J Epidemiol Community Health June 2011 Vol 65 No 6
entire developed world’s RAs.7 When GLP was first proposed, industry must have known that independent scientists are, before peer review, reluctant to share raw data or methods with grant competitors; and so realised that the new requirement was a golden opportunity to thoroughly exclude very inconvenient data from review. Indeed, the agencies defined good data quality as GLP, that is, industry data. In short, the GLP mandate instantly excluded hundreds of thousands of competent studies from chemical RA. GLP’s ubiquity causes others to assume that it means quality datadfor example, industry’s popular Klimisch scoring of toxicity data quality, which assigns GLP the top rank,8 or in the comprehensive EU chemical safety law, REACH, and many other laws. Industry’s toxicity studies have failed to modernise for nearly 100 years,9 still largely relying on the visible light microscope to see gross changes in slides of organ tissues. Many biological end points are ignored, and their standards on dosing and test animals have not advanced nearly as far as those of independent researchers. Very high doses are used (to assure statistical significance, due to insensitivity of the assays), but such near-poisoning levels may have little to do with what happens to organisms that are exposed to real world doses.and which go untested. Also, dosing misses the complexity of development, the cause of many diseases. Last, test animals are killed before old age, masking most developing diseases. In short, GLP tests use protocols that cannot find toxicity. Yet biochemistry is often a low-level signal,10 thus potentially disrupted by very low doses of petrochemicals which life did not evolve with. In fact, endocrine and other signals are often stronger at low dose than at high dose,11 and the common assumption that there is a safe dose below which no significant toxicity occurs is dead wrong.12
BPA is one such an agent, and the controversy over its hazards has, unusually, caused scientists to criticise GLP as the cause of a dangerous ‘false negative’ error in society. The European Food Safety Authority’s (EFSA) recent finding that BPA oral exposure is still safe1 once again required them to exclude hundreds of valid non-GLP results which find BPA toxic at low levels.5 Nor is BPA nearly as thoroughly excreted by humans as its makers, EFSA and the US-FDA claim.13 In fact, industry’s GLP toxicity studies seem designed not to find BPA toxicity.14 Both these agencies failed to request raw data or methodologies of any independent BPA researcher; instead they as always relied on GLP as the marker of reliable data.14 Such a chemical safety system is a failure, but society continues to rely on nearly 100-year-old methods to judge the risks of chemicals. Disastrously, the ‘GLP shield’ discussed above causes hundreds of thousands of independent results (which tell an opposite story) to be excluded from RA. Animal toxicity tests are meant to detect health risks before we widely distribute a risky agent, but we have completely failed to act on the massive evidence database of the independent literature. By contrast, epidemiological correlations of chemicals with disease (of prospective design and with improving exposure assessment and confounder control) are a critical part of the evidence required to assign causation; however, unfortunately epidemiology comes after the approval of chemicals, which is fatally flawed by GLP. All scientists should vehemently object that their main method to assure data qualitydpeer review and publicationdhas been abandoned for a system (including GLP) which claims that a massive financial interest yields the highest quality data. They should demand that their work be evaluated and used in chemical RA. Also, regulatory agencies should be able to demand, and be required to evaluate, the easily transmitted raw data and methods of independent researchers (with confidentiality protections for their prepublication needs). Competing interests The author receives consultation fees from NGOs who advocate for the public’s interest in health. Provenance and peer review Commissioned; externally peer reviewed. Published Online First 15 February 2011 J Epidemiol Community Health 2011;65:475e476. doi:10.1136/jech.2010.127761 475
Commentary
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European Food Safety Authority. EFSA updates advice on bisphenol A. http://www.efsa.europa.eu/ en/press/news/cef100930.htm (accessed Nov 2010). Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research. JAMA 2003;289:454e65. Fagin D, Lavelle M. Center for Public Integrity. Toxic Deception: How the Chemical Industry Manipulates Science, Bends the Law and Endangers Your Health. 2nd Edition. Monroe, ME: Common Courage Press, 1999:190. Swaen GM, Meijers JM. Influence of design characteristics on the outcome of retrospective cohort studies. Br J Ind Med 1988;45:624e9. vom Saal FS, Hughes C. An extensive new literature concerning low-dose effects of bisphenol A shows
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the need for a new risk assessment. Environ Health Perspect 2005;113:926e33. Baldeshwiler AM. History of FDA good laboratory practices. Quality Assurance Journal 2003;7:157e61. Organization for Economic Co-Operation & Development. Good Laboratory PracticedOECD Principles and Guidance for Compliance Monitoring. Paris, France: OECD Publishing, 2010:140. Klimisch HJ, Andreae M, Tillmann U. A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regul Toxicol Pharmacol 1997;1:1e5. Klaasen C, ed. Casarett & Doull’s Toxicology: The Basic Science of Poisons. 7th Edition. New York City: McGraw Hill, 2007:1280. Ray LB, Gough NR. Orienteering strategies for a signaling maze. Science 2002;296:632e3.
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Welshons WV, Thayer KA, Judy BM, et al. Large effects from small exposures. I. Mechanisms for endocrine disrupting chemicals with estrogenic activity. Environ Health Perspect 2003;111:994e1006. Sheehan DM. No-threshold doseeresponse curves for nongenotoxic chemicals: findings and applications for risk assessment. Environ Res 2006;100:93e9. Vandenberg LN, Chahoud I, Padmanabhan V, et al. Biomonitoring studies should be used by regulatory agencies to assess human exposure levels and safety of bisphenol A. Environ Health Perspect 2010;118:1051e4. Myers JP, vom Saal FS, Akingbemi BT, et al. Why public health agencies cannot depend on good laboratory practices as a criterion for selecting data: the case of bisphenol A. Environ Health Perspect 2009;117:309e15.
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