What exactly don’t we know?

Vandenberg et al. (Is everything we think we know about chemical toxicity wrong?) conclude that there is consistent evidence that dioxin, atrazine, BPA and perchlorate have effects at low doses and, furthermore, that the effects observed depend on the dose.

If correct, the consequences for regulatory toxicology are fundamental: if low dose effects cannot be inferred from high-dose studies then the method used to evaluate almost all chemicals for safety must be unsound.

Historically, regulatory toxicology has tested chemicals at high doses and lowered the dose until no effect is observed, at which point this dose is divided by between 50 and 1000 to produce the acceptable daily dose which human exposure is not meant to exceed (the Tolerable Daily Intake, or TDI). If a chemical can be used in such a way as to not expose people to a dose higher than the TDI, then its use is accepted.

However, if chemicals act inversely to their concentration, then their effect on health at low doses cannot be inferred from their effect at high doses: the TDIs become invalid, and a rethink of the design of toxicological studies becomes necessary.

New methods

Vandenberg et al. make four recommendations for the future design of low-dose toxicological studies:

1. Choice of dose ranges. Currently, regulatory guidelines only require that three doses be tested, and whether or not these doses produce circulating levels of the test compound which reflect those seen in humans is often unclear. Studies need to ensure they are genuinely testing low doses of chemicals.

2. Timing of exposure. In general, but not always, developmental exposures have permanent organisational effects, while post-puberty exposures are mainly activational and cease upon end of exposure to the compound in question. The organisational effects observed depend heavily on the timing of exposure, so not only is dose range important, the timing of administration is critical as well.

3. Importance of end-points being tested. Guideline protocols generally look at gross changes to animal health or reproductive outcomes, such as organ weight, death, mortality, and some histopathological analysis of organs. Chemicals acting at low doses are not rapidly lethal but affect a number of end-points important to health, so the end-point selected needs to be relevant to potential effect, rather than being a gross indicator of well-being.

4. Study size. Much is made of how detecting subtle effects from low-dose exposures requires massive numbers of animals. This is not, in fact, the case: when an appropriate end-point is selected, the number of animals used in a study is determined by statistical factors relating to certainty of finding and is therefore variable, rather than the absolute numbers required in the current standardised protocols.”