Impasse on BPA: different facts – or different values?

November 7, 2011 at 8:43 pm | Posted in Feature Articles | 1 Comment

Animal studies suggest exposure to even very low levels of BPA may be harmful to health. Regulators, however, generally describe these studies as being irrelevant to risk assessment. Are they really meaningless? Or is there something the regulators need which the studies aren't giving them?

We are coming towards the end of two years of hearing very mixed messages about the safety of BPA.

On the one hand, in 2009 the US Endocrine Society concluded there is a strong basis for concern about the human health effects of endocrine disrupting chemicals such as BPA (Diamanti-Kandarakis et al. 2009).

In March 2010, Denmark introduced restrictions on the use of BPA in food contact materials for children under 3 years of age. The same month saw Health Canada prohibit the use of BPA in baby bottles.

On the other hand, in October of 2010 the European Food Safety Authority (EFSA) found none of the new research on BPA indicated a need for reducing its tolerable daily intake (TDI) of the substance, or that current use poses a health risk to anyone in the general population (EFSA 2010). The UK Food Standards Agency backed EFSA’s findings.

In 2011 the Advisory Committee of the German Society of Toxicology (ACGST) concluded in a review of the criticisms of EFSA’s evaluation of the safety of BPA that none of the counter-arguments to maintaining the existing TDI are compelling (Hengstler et al. 2011).

These are all bodies with substantial scientific expertise, yet clearly divided in opinion between those who believe BPA is safe, at least at current exposure levels, and those who believe exposure to BPA should be reduced. They all have access to roughly the same data, which they should be able to analyse objectively. So the question is: how has this happened?

The place to look for the reason for the impasse may well be in each side’s conception of what counts as adequate science in evaluating and responding to the possible threat to health posed by BPA. To this end, Health & Environment interviewed two scientists with opposing views on BPA regulation.

On one side of the debate is Professor Jan Hengstler, Project Group Leader for Systemic Toxicology at the University of Dortmund’s Leibnitz Research Centre for Working Environment and Human Factors (IFADo), and corresponding author of the ACGST review of the safety of BPA, which endorsed the existing TDI for BPA.

On the other is Professor Gilbert Schoenfelder, a pioneer of BPA biomonitoring at the German Institute for Clinical Pharmacology and Toxicology (and, like Hengstler, also a member of the German Society of Toxicology), who believes that BPA is inadequately regulated and likely to have a range of harmful effects on health.

Sound science?

Hengstler describes the process by which toxicologists assess the safety of BPA: “You do animal experiments to determine the level at which BPA has no observable adverse effect (NOAEL) and divide that by several safety factors to obtain a TDI for humans.” Regulators then ensure that these levels are not exceeded in humans.

Hengstler repeatedly emphasises how regulatory toxicological studies and reviews are designed to derive a safe dose level for BPA with a very high degree of statistical certainty. “The criteria for scientific validity of a regulatory study is tighter than those required in a peer-reviewed journal,” he says, explaining that in journals, 5% confidence intervals provide enough surety that a result is not a fluke and sufficient for it to be published.

Because regulatory studies are designed to have the last word on an issue, they have to eliminate, as a far as possible, the chance of their findings being false positives. These confirmatory studies have much tighter confidence intervals, with much larger groups of animals being studied.

The confidence of toxicologists in the findings of a study are further enhanced by following agreed protocols for studying harm such as the standardised Organisation for Economic Co-operation and Development (OECD) guidelines (or see e.g. EFSA guidance on oral toxicity studies). More controversially, Good Laboratory Practice (GLP) compliant studies are also preferred by regulators because the exhaustive documentation is believed to further enhance a study’s reliability.

The need for certainty is also manifest in the definition of “adverse effect” as captured in the NOAEL. “It is not enough to see that a compound causes a change, we need to be sure that the change is adverse,” says Hengstler. “For example, glucose alters gene expression but these changes aren’t associated with adverse effects.” Any potential indicators of harm, or biomarkers, therefore “need to be validated if they are to be used for regulatory purposes,” says Hengstler.

Without formal agreement on what the studies mean for humans, a toxicologist cannot use a study to modify the TDI. This is clear in EFSA’s Opinion on BPA: “The Panel… concluded that no new study could be identified, which would call for a revision of the current TDI… The Panel noted that some studies  conducted  on  developing  animals  have  suggested  other  BPA-related  effects  of  possible  toxicological relevance…  At present the relevance of these findings for human health cannot be assessed.”

Of course, statistical certainty means very little if precise studies are looking at the wrong evidence. A study protocol can grant almost absolute certainty that exposure to BPA has no effect on the size or basic function of the liver in a lab animal. This will not, however, tell you anything about BPA’s toxicity in the reproductive or cardiovascular system.

Toxicological testing of BPA is of course more complex than that. Nonetheless, many scientists, of which Gilbert Schoenfelder is one, are unconvinced that the tight standards of regulatory studies have produced accurate assessments of the safety of a substance such as BPA.

These scientists argue that regulatory studies are poorly-equipped for evaluating the safety of BPA, looking for effects which low doses of BPA can’t produce, and missing the toxic effects which low doses of BPA actually produce.

“Independent studies find all sorts of things,” says Schoenfelder, “and try to get clear on what this means for humans. The risk assessors just say they don’t know what this means for humans, so disregard it.”

Schoenfelder agrees about the need for standardised protocols. “We need direction for companies on the basis of what could, at the moment, be the most sensitive test system to exclude a risk to humans. This is why we have study guidelines for industry,” he says. “But we have to ask: how old is the guideline? Are there techniques which are more sensitive? If we have data and information from studies which don’t conform to guidelines, then what is the meaning of those studies?”

Political action

Hengstler believes exploratory research should precipitate discussion of whether more research is needed or study guidelines should be changed: “If you find evidence of an adverse effect it should of course be published, but it does not mean that a single, published exploratory study is a basis on which to ban a compound. Such studies are the start of a discussion process.

“There is nothing wrong with publishing these, but if they aren’t reproduced you have to conclude that the findings are a false positive – which is no basis for regulation.”

Hengstler’s position fails to satisfy the likes of Schoenfelder because they feel that uncertainty in the TDI should not simply start discussion or trigger a more precise research programme, but rather constitutes a reason for doubting the TDI at all.

“What is the meaning of a guideline compliant study if it doesn’t look at things which are being exposed by new research?” asks Schoenfelder. “If there is a good, published paper then it counts as positive evidence, and then we need more research for an explanation or a mechanism, or new research on the topic.”

It is adherence to the exacting standards of regulatory toxicology which toxicologists equate with scientific rigour: where research scientists see uncertainty and a questionable TDI, regulatory toxicologists see a carefully-calculated, validated TDI which could in future be subject to change but only if the data is certain enough to warrant it.

Regulating without certainty, as Schoenfelder advocates, is anathema to the toxicologists’ approach, and may explain some of the resistance to regulation of BPA and description of moves in favour of its regulation as political rather than science-based.

Since both Schoenfelder and Hengstler favour rigour in risk assessment, their difference in opinion can be interpreted as resulting from their attitudes about what regulatory steps should be taken in the face of fresh evidence of possible harm, before guidelines have been developed.

One may not agree with recent moves to restrict the use of BPA. However, there is nothing inherently unscientific about acting early on preliminary findings if these undermine confidence in the accuracy of a TDI, so it is probably not helpful to describe the precautionary moves by Denmark, France and Canada as such.

Regardless, regulation seems to be going the way of Schoenfelder’s precautionary approach. The temporary Danish restrictions on use of BPA, citing continuing uncertainty about the neurodevelopmental effects of BPA, the similarly temporary French restrictions, and also the recommendations of Health Canada, all point to a change in approach to risk assessment.

This is, if new evidence emerges which casts doubt on the TDI of a substance, then use of the substance is restricted until the methods for evaluating the substance have been updated, with restrictions due for reversal if it is subsequently proven safe.

This change matches the shift in who is responsible for the safety of chemical products, formalised in REACH, from the onus being on the regulator to prove that a substance is harmful before it can be restricted, to a manufacturer having to prove a substance is safe before they can introduce it to the market.

REACH is unique insofar as, to a greater or lesser extent, it forces manufacturers to demonstrate that their products have an adequate pedigree of safety before they can be brought to market. The case of BPA demonstrates there is not as much confidence in the existing guidelines and study protocols as some parties to the debate about chemical safety might think there should be.

Controversy surrounds BPA precisely because of the lack of agreement over what counts as an adequate evaluation of a chemical’s safety. This is not politics. It is not even, strictly speaking, just about the safety of BPA. Representing it as being a simple issue of science vs. politics obscures much of the common ground between the two sides on the bigger issue of the modernisation of chemicals policy, of which BPA happens to be the poster-child.

Common ground?

In spite of their differences, during interview both Hengstler and Schoenfelder independently described the need for transparent, reliable testing based on robust data; the need for rapid development of guideline tests to incorporate new research findings; and the need for easy access to all relevant data and transparent evaluation open to the public.

Regardless of how one feels about BPA, there may be a way forward yet.

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  1. […] involves a lot of educated guesswork. The process is therefore not without its critics (as readers of H&E will know). The problem is, if things did not already look unreliable enough, the […]

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