Issue 24 – Toxicology

Issue 24, March 2010 (scroll down for this month’s articles): Are all things poison? Rethinking safety standards for low doses of chemicals :: Scientific society urges changes to basic principles of risk assessment :: New studies associate non-stick chemicals with high cholesterol and thyroid disorders :: Plus 5&5, our revamped round-up of the best news and science from February.

Are all things poison? Rethinking safety standards for low doses of chemicals

One way in which hormonally-active chemicals can exhibit unpredictable dose-responses at levels below those tested for health effects. Click to enlarge.

Paracelsus, a 16th-century physician, is said to have established the basic principle of modern toxicology with the saying, “All things are poison and nothing is without poison; only the dose makes a thing not a poison.”

Developments in endocrinology are confirming that for some chemicals, while the dose does indeed make the poison, the phrase “all things are poison” may be too close to the mark for comfort.

The key assumption governing regulatory toxicology is that safe levels can be established by testing the effects of high doses and subsequently reducing the dose to the lowest level at which there is an observed adverse effect. This is the LOAEL, or Lowest Observed Adverse Effect Level.

The LOAEL dose in animals, usually mg/kg/day in rodents, is translated into a tolerable dose for humans by dividing by “uncertainty factors”. A factor of 10 is intended to take into account differences in metabolism; a further 10 human variability, and 10 more is supposed to allow for susceptibilities such as genetics or pregnancy.

Sometimes an extra factor of 2 or 5 is taken into account while further risk assessment takes place, or to allow for the difference between adults and children, but in general the safe dose for humans is determined by dividing the LOAEL by 1,000.

For bisphenol-A (BPA), the controversial plastic additive common in food packaging, the LOAEL in mice is 50mg/kg/day. Dividing by 1,000 gives the “safe” dose, or Tolerable Daily Intake (TDI) for humans, of 0.05mg/kg/day. Regulations are then put in place in an effort to ensure the public is not exposed to BPA at concentrations above this level.

None of this would work, of course, if chemicals were found to behave unpredictably at low levels and show effects at doses substantially beneath the LOAEL. Unfortunately for the effectiveness of safety regulation, this is exactly what seems to happening with chemicals which interfere with hormone control systems in the body.

For example, BPA has been found to have a greater effect on prostate tumour proliferation at 1 nanomole concentrations than it does at 100 nanomoles (Wetherill et al. 2002). The plastic softener DEHP has been found to up-regulate aromatase expression in neonatal male rats at doses above the LOAEL, but down-regulate it at doses far below the LOAEL (Andrade at al. 2006).

In an extreme example of different high-dose and low-dose effects, arsenic causes multiple organ failure at high doses, suppresses glucocorticoid hormone induction at low levels, yet enhances the same process at lower levels still (Bodwell 2004).

The point for regulating chemical safety is these studies show that low-dose effects cannot be extrapolated from high-dose testing: low-dose experiments falsify the basic assumption on which the regulatory system is built. At the very least, it seems chemicals should be tested for health effects at exposure levels relevant to those found in the human population.

Incorporating endocrine science into chemicals safety policy represents a hefty regulatory challenge. However, the number of health conditions now linked to hormonal effects of chemicals including prostate and breast cancers, behavioural and attention deficit disorders, miscarriage, heart disease and type II diabetes (see Myers et al 2009 for a fuller list).

Because of the profound implications for public health, organisations including the American Medical Association and the Endocrine Society are now urging that human exposure to endocrine-disrupting chemicals be minimised.

Scientific society urges changes to basic principles of risk assessment

The American Chemical Society (ACS) has formally urged for change in management of the health risks posed by endocrine-disrupting chemicals (EDCs).

The ACS highlights how low doses of EDCs can have different effects to higher ones, stating this makes it “impossible to predict” their effects at low concentrations.

Although this behaviour is well established in medical endocrinology, the ACS believes these responses “are less well understood” in traditional toxicology.

Currently, health risks of chemicals are assessed by testing the effects of exposure to high doses, from which a safe-dose threshold is calculated where the chemical is assumed not to pose a threat.

The ACS calls for specific improvements in testing for endocrine disruption, particularly in dose ranges to which humans are typically exposed, and the expansion of education regarding endocrine disruption within the scientific community.

In a parallel development, the US Maryland DC Society of Clinical Oncology published a position statement supporting efforts to remove the endocrine-disrupting chemical bisphenol-A (BPA) from child-care products and toys.

In the most unambiguous statement of its type to date, the Society says: “Make no mistake about it: the research is clear and reproducible in multiple studies. This product is dangerous.”

New studies associate non-stick chemicals with raised cholesterol levels and thyroid disorders

A common chemical byproduct of the manufacturing process of non-stick coatings used in cookware and stain-resistant fabrics has been associated with a range of health problems, according to new studies published last month.

In the first study, British researchers looked at how blood-serum levels of the chemicals PFOA and PFOS correlated with thyroid disease in 3974 US adults, finding that people with higher levels of the chemicals were more likely to be treated for thyroid problems.

In the second study, designed to look at concerns that PFOA and PFOS may disrupt body fat and weight regulation, researchers confirmed other findings that exposure to the chemicals increases cholesterol levels, though found no consistent association with body size.

Both studies drew on US National Health and Nutrition Survey (NHANES) data, a 40-year-old US health and biomonitoring programme which provides a rich data set for epidemiologists. There is as yet no such equivalent in Europe.

A third study examining how PFOA exposure may be associated with risk factors for cardiovascular disease, found that adults with higher levels of PFOA in their blood were more likely to have elevated levels of uric acid.

5&5: Five news and five science highlights from February

5 Stories

Bans sought for BPA in baby and toddler products: USA Today reports on how the number of US states seeking restrictions on bisphenol-A now totals 12

Nordic Council refers to industry/NGO list for chemicals to avoid: The SIN list is an expanded list of hazardous chemicals drawn up, with industry support, to go beyond the limited set of chemicals restricted under REACH.

Human biomonitoring at heart of US toxics law: The New York Times talks up the importance of human biomonitoring for improving understanding of how chemical exposures affect health.

Alternatives to BPA containers not easy for US foodmakers to find: The Washington Post describes how the ubiquity of BPA means that even food packaged in theoretically BPA-free containers is showing traces of the chemical.

US experts want tests to determine role of chemicals in breast cancer: US experts called Friday for toxicity tests on chemicals they suspect play a role in the development of breast cancer, a leading cause of death in American women.

5 Studies

BPA-induces epigenetic changes resulting in oestrogen hypersensitivity: Prenatal BPA exposure caused mice in this study to exhibit uterine hypersensitivity to oestrogen throughout adulthood, indicating long-lasting epigenetic changes to developmental programming.

What causes autism? Exploring the environmental contribution: The journal Current Opinion in Pediatrics explores how early environmental exposure may contribute to autism, given that genetic factors explain only a fraction of autism cases.

Perinatal exposure of rats to BPA affects fertility of male offspring: Rat study showing that exposure to BPA at levels within the range of human exposure lowers male fertility in adulthood and affects the germ line, also reducing the fertility of offspring.

Neonatal pesticide exposure alters cell development and could make rats fat: Animal study finding indications that organophosphates “alter the trajectory of hepatic cell signaling in a manner consistent with the observed emergence of prediabetes-like metabolic dysfunction.”

Body burdens of brominated flame retardants and other compounds in US girls: A potentially significant exposure study showing differences between two US states, and that exposure is widespread in prepubescent and pre-menses girls.

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