Toxicology-based recommended exposure limits

New concept

Toxicology-based recommended exposure limits

The Dutch government’s policy on the control of substances is intended to protect human health against the possible adverse effects of substances released into the environment as a result of human activity. To this end, limits are set on substance concentrations in soil, water, air, food and so on. The limits imposed by the government are in their turn based on health-based recommended exposure limits formulated by experts. Exposure to the concentration of a substance equal to or lower than that limit, even for long periods, may reasonably be expected to prevent damage to the health of exposed individuals and their offspring. For some substances, with the framework of the substances policy of the government, toxicology-based recommended exposure limits are derived, instead of health-based recommended exposure limits; given continued exposure at a level equal to such a limit, the chance of an individual suffering a certain effect may reasonably be expected not to be greater than specified in the limit. The chances specified in the limits are small. It is standard practice in the Netherlands to set toxicology-based recommended exposure limits for genotoxic carcinogenic substances; this policy is designed to ensure that the additional chance of an individual contracting cancer may reasonably be expected not to exceed one in a million, given lifelong exposure. (Such additional risk is considered by the government to be negligible.) A health-based recommended exposure limit may be regarded as a particular form of toxicology-based recommended exposure limit, namely a form which specifies a level of exposure at or below which the chance of any adverse health effect may reasonably be expected to be nil.

In addition to prescribing concentration limits, the government sets various other standards, including intervention levels. An intervention level specifies the concentration of a substance at which the government considers it appropriate to intervene (or for others to be obliged to intervene) to protect public health. Intervention levels too are based upon toxicology-based recommended exposure limits; exposure under the specified conditions at a level corresponding to that specified in the limit may reasonably be expected to adversely affect the health only to a certain - specified - extent. Intervention levels are set for periods of increased atmospheric pollution, for example.

This report

In this report, the Health Council’s Committee on Health-based recommended exposure (further on: the Committee) limits provides a general description of the way in which toxicity data and the results of epidemiological research can be used to formulate toxicology-based recommended limits for exposure to substances. The report marks the first step towards the revision and extension of what is widely known as the Van Genderen Report, published by the Health Council in 1985. A review of the Van Genderen Report was felt to be desirable in the light of subsequent scientific debate regarding the formulation of health-based recommended exposure limits. Another consideration was the government’s increasing need for information regarding the effects associated with certain, often unavoidable, levels of exposure and regarding the incidence of such effects – i.e. the response level – within the exposed population.

This report is not intended as an exhaustive treatise on the subject of exposure limit formulation. In keeping with the wishes of the Health Council’s President, the Committee has endeavoured to indicate the respects in which the Van Genderen Report would benefit from revision or expansion, and to highlight areas warranting the Health Council’s further attention.

The critical nature of the exposure-response relationship

At present, toxicity research tends to concentrate on identifying levels of exposure at which adverse health effects are unlikely. The Committee wishes to see the emphasis shifted to increasing insight into the link between exposure and response. If enough is known about the exposure-response relationship for a given substance, a toxicology-based recommended exposure limit may be formulated on a systematic basis. The approach advocated by the Committee is illustrated below.

The formulation of a toxicology-based recommended exposure limit involves a number of stages. First, the available animal experiment data and epidemiological data are analysed with a view to deriving exposure-response functions for those effects which may be considered adverse in relation to human health. Uncertainty factors are then applied to produce an exposure-response function which will form the basis of the toxicology-based recommended exposure limit. The uncertainty factors take account of the uncertainty associated with, for instance, the extrapolation of conclusions regarding human exposure from animal data and sensitivity differences within the population to which the limit will relate. This procedure is intended to exclude any reasonable possibility of the health implications of exposure being underestimated.

Integrated toxicity profiles

Data on the health implications of exposure to a substance is derived from various sources. The Committee recommends that data from these sources be studied on an integrated basis as far as possible. In this context, models of the absorption, distribution, metabolism and excretion of a substance in the body (biokinetic models) and the effects of a substance or its metabolites in a target organ (biodynamic models) can be very valuable. Analysis will also benefit from general insight into the link between a substance’s chemical structure and its effects. This approach, referred to in this report as the construction of an integrated toxicity profile, is felt by the Committee to be the best way of ensuring optimal utilization of available data and effective and efficient control of toxicity research. Greater efficiency can in turn reduce the need to conduct experiments on laboratory animals. The data basis of an integrated toxicity profile is illustrated below.

Recommendations

The Committee makes the following recommendations regarding the construction of integrated toxicity profiles:

• The development of improved exposure estimation methods for use in epidemiological research and the use of biomarkers in the measurement of exposure and the early detection of effects should be encouraged.
• Greater importance should be attached to the use of data on substance biokinetics and biodynamics in the extrapolation of conclusions regarding human exposure from animal data and in predicting the outcome of exposure via one route from information regarding another.
• More detailed information should be gathered regarding the reliability of the present biokinetic and biodynamic models.
• The use of such models in protocol toxicity research should be encouraged so that such research may be guided by decision trees and efficiency thereby improved.
• The development of methods and procedures for research using volunteer subjects into the biokinetics and metabolism of substances in the body should be encouraged.
• The scope for using structure-activity relationships in the assessment of exposure-related human health risks should be investigated, since such models could increase the efficiency of toxicity research.

The formulation of health-based recommended exposure limits

In the Netherlands and elsewhere, health-based recommended exposure limits are normally formulated using the NOAEL/UF¹ method. (This method is the foundation of the approach advocated by the Van Genderen Committee.) A health-based recommended exposure limit is calculated by dividing the NOAEL for the substance in question by a factor which takes account of uncertainties in the available data and in the extrapolation from that data of findings pertinent to the population group to which the limit is to apply. No other methods are in widespread use. The Committee believes that limits should be formulated using a method which makes systematic use of data on the relationship between exposure and response; the so-called ‘benchmark dose’ (BMD) method is felt by the Committee to be particularly promising. However, before this method can be regarded as a viable alternative to the established method, further practical evaluation is required. The Committee therefore recommends that new health-based recommended exposure limits be formulated using the BMD method for various substances which have already been assessed for occupational health and safety and environmental protection purposes. In this way, it would be possible to identify the data required to apply the method in practice and the issues relevant to the extrapolation of health-based recommended exposure limits from BMDs.

Subjects requiring further attention

The Committee believes that more detailed Health Council reports on the following subjects would be valuable:

• The interpretation of epidemiological research findings.
• Integrated toxicity profile construction methodologies and the way in which the various types of toxicity research are interrelated.
• Techniques for taking account of the toxicology of (complex) chemical mixtures and of substances in combination with co-factors such as noise, odour, heat, vibration and psychosocial factors when formulating toxicology-based recommended exposure limits.
• The application of response data in the formulation of health-based recommended exposure limits, perhaps once the scope for using the ‘benchmark-dose’ method has been investigated (in which case particular attention should be given to the extrapolation of exposure-response curves into the exposure regions for which data is not available).

The Committee believes that the recommendations contained in the Van Genderen Report remain valid. The desirability of formulating health-based recommended exposure limits in accordance with a transparent procedure is currently widely acknowledged; such a procedure is no less desirable in relation to other types of toxicology-based recommended exposure limit. Nevertheless, the report’s findings do require expansion in some areas, as the Committee has indicated. If, as advocated by the Committee, the emphasis of toxicity research were shifted onto the exposure-response relationship, all types of substance could be brought within a single assessment framework.

^{₁ NOAEL stands for 'noobserved adverse effect level' and UF for uncertainty factor. The NOAEL is the highest level of exposure to a given substance at which no adverse effect on the health of humans or laboratory animals is observed.}