Is there a better way of assessing the risks which chemicals may pose to human health?

January 25, 2011 at 6:25 pm | Posted in Feature Articles | 4 Comments

The adequacy of the process for assessing risk to human health posed by chemicals is coming under increasing scrutiny. In this month’s feature article, we examine some of the criticisms of risk assessment and the relative merits of moving towards a more hazard-based approach to chemical regulation.

Breast cancer is the leading cancer killer among women aged 20-59 years in higher-income countries, according to the WHO. Although exposure to environmental chemicals is increasingly thought to be a risk factor for the disease, regulators do not yet screen chemicals for their ability to cause or promote breast cancer before they allow them to be marketed.

Decisions about allowing chemicals to be used are almost always based on risk assessment (RA). Risk assessment is the attempt to quantify potential harm posed by a human activity. Financial risk assessment is the potential loss implied by carrying out an activity multiplied by the likelihood of the loss. The higher the number, the higher the risk and the more stringent the measures which need to be taken to reduce the risk. If measures cannot be taken to reduce the risk of loss to acceptable levels the activity is considered financially unviable.

For chemicals, risk assessment is concerned with the probability that a substance will cause harm under carefully specified conditions within a defined time-frame. The likelihood of illness or death resulting from the use or manufacture of a chemical should not exceed a certain threshold; this might be something like causing only one fatality over 1,000,000 lifetimes of use.

A risk assessment has three basic parts: a hazard assessment, which identifies the health consequences of an exposure; a dose-response analysis, which determines the dose at which those consequences are likely to occur; and an exposure assessment, which looks at whether or not any populations or sub-populations are likely to be exposed to higher levels than those calculated as safe in the dose-response analysis. Regulators then attempt to reduce all populations’ exposure below the estimated harmful dose.

Risk assessments are not, however, foolproof. The UK Health Protection Agency, in its characterisation of the process, warns that: “It is important that assessors, users, regulators and members of the public recognise risk assessment may not always provide a compelling or definitive outcome.”

One way in which RA can fail is during the hazard identification process, simply because a chemical may present an unknown hazard which is not accounted for during the RA process. For example, the European Food Safety Authority’s (EFSA) 2006 opinion on the safety of bisphenol-A was mainly concerned with toxicity studies measuring organ weight changes in rats and liver toxicity in mice.

Although the gross end-points accepted as relevant to RA do shift, with extra attention paid in EFSA’s revised opinion in 2010 to the potential neurotoxicity of BPA, the process is slow and risk assessors tend to demand certainty that a chemical has a particular gross adverse effect before the effect is incorporated into the RA as a recognised hazard.

A different approach

Table showing the biological processes which, if altered by exposure to chemicals, may be expected to increase the risk of breast cancer. The BCCP argues that chemicals should be screened for and prioritised for regulation on their ability to alter these processes. Click to enlarge.

Attention has recently become focused on whether or not the risk assessment process is even looking at the right kind of health end-points for determining whether or not a chemical poses a risk to human health. As one example, the Breast Cancer and Chemicals Project (BCCP) of the University of California San Francisco, is concerned that relatively crude assays, such as those cited by EFSA, are not accurate indicators of increased risk of breast cancer, and is looking instead at whether or not hazard assessment can be done on the basis of the ability of chemicals to alter the underlying biological processes which result in those health outcomes (Schwarzmann and Janssen, 2010).

The concept central to the Panel’s approach to hazard identification is that of “toxicity endpoints”. Instead of crude health outcomes, toxicity endpoints are alterations to the biological processes associated with development, progression or susceptibility to breast cancer (in this case, general carcinogenesis, endocrine disruption, and altered development and maturation of the mammary gland). The Panel then identified a series of toxicity test assays capable of screening chemicals for their ability to alter or perturb the toxicity endpoints.

Dr Sarah Janssen, one of the report authors, explains: “The key point of the project is the model the panel developed. Normally, toxicity testing starts with a mechanism of action and tries to work out how this can influence a particular disease. This time we started with the disease, and asked what are the biological processes which are involved in the disease, and which alterations to these processes elevate risk of the disease, and then how chemicals might affect these alterations.”

The future of risk assessment

The BCCP's schema for prioritising chemicals for regulatory testing (top) and identifying chemicals hazards (bottom). The hazard identification process maximises speed and minimises animal testing by using in vitro assays where possible. Click to enlarge.

Because the BCCP proposal looks at upstream endpoints which modify risk without necessarily being clear by how much or whether or not the end-points count as “adverse” effects, it amounts to a radical overhaul of toxicity testing in chemical regulation and is likely to be a difficult to sell to regulators.

EFSA seems firmly wedded to the approach it followed in its 2006 Opinion on BPA, in which it quotes the UK Committee on Toxicology saying: “The effects (of low dose BPA administration) on reproductive organs may represent very sensitive intermediate biomarkers that indicate the need for further studies, but cannot be defined as “adverse”. Overall the Committee concluded that it is not appropriate, at this time, to base human health risk assessment on these effects” (2006 Full Opinion, p44).

There are, however, both logical and pragmatic arguments for such a move. The IARC definition of carcinogen, as a chemical or environmental agent “capable of increasing the incidence of malignant neoplasms, reducing their latency, or increasing their severity or multiplicity” allows chemicals to be interpreted as carcinogens if they can be shown to alter tissue structure, cellular function or immune response in such a way as to make tumour growth more likely.

Treating chemicals as one factor among many which may act alone or in combination to initiate neoplasms or accelerate their growth lends itself to a hazard-oriented approach to assessing risk to health posed by chemicals. This would make it easier for RA to incorporate evidence from mechanistic studies looking at alterations to biological pathways, where at the moment RA is forced to dismiss as irrelevant the studies which, although they provide evidence of harm, do not provide clear data which can be fed into a risk calculation.

A hazard-based approach which is more accepting of mechanistic studies could also allow regulators to address some of the practical issues which are becoming more urgent as REACH enters into force in Europe and chemicals regulation in the US becomes tighter. In particular, there is a growing need for a battery of tests which will identify the potentially harmful substances among the tens of thousands in use, and will at the same time limit animal testing as much as possible.

The US National Academy of Sciences has already recommended that toxicity testing shift its emphasis from whole-animal test protocols to more efficient mechanism-based chemical screening. Such changes mean toxicity testing is likely to become ever-more dependent on high-throughput screening (HTS), a technique key to drug development which it allows a huge number of synthetic compounds to be rapidly tested for potential biological effects.

The difference in chemical regulation is, where HTS is used by pharmaceutical companies to select biologically active molecules for further development, for chemical regulation the same processes would be used to detect biologically active commercial chemicals which can then be prioritised for regulation.

Research would likely have to shift focus to a better understanding of disease mechanisms in order to identify suitable toxicity endpoints, and the development and validation of assays which can be used to detect how chemicals can alter them. However, if in vitro data can be worked into the regulatory process as a robust way of testing chemicals for potential hazard, the process of prioritising chemicals according to potential hazard could be greatly accelerated and risk assessment methods adapted to better protect public health from the emerging hazards posed by modern society’s use of chemicals.

Read the BCCP report here.

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  1. […] Is there a better way of assessing the risks which chemicals may pose to human health? […]

  2. […] other possible solution is to assess chemicals according to total effect on a disease end-point (see e.g. H&E #34). This has precedent in ecotoxicology, where simply affecting, for example, reproductive potential […]

  3. […] be overestimated. We have covered these shortcomings a number of times in H&E (see e.g. #42, #34) and there are detailed critiques in the peer-reviewed literature (e.g. Myers at al. 2009). Current […]

  4. […] 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 possibility that some […]


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