General Principles of Risk Assessment

Determination of the risks posed by endocrine active compounds (endocrine toxicants) to humans is essential to monitor endocrine-related health outcomes and to develop risk management strategies for endocrine toxicants that will protect population health.

Risk
The determination of risk, or 'risk assessment', includes a stepwise, logical framework to properly identify, characterize and measure risk. Risk posed by exposure to an environmental toxicant depends on the probability of its occurrence and its associated consequences. Severe outcomes such as chronic debilitating diseases or death are of greater significance than acute illnesses of minor consequence. Similarly, the frequent occurrence of an adverse health effect may be of greater concern compared to the occasional occurrence of another health effect.

Adverse Effects
As the consequence of exposure to environmental toxicants contributes to the overall risk of exposure, this consequence or outcome must be defined. Generally, the consequence of exposure may be described in terms of the adverse health effects induced. Such effects are further characterized by factors such as their nature, severity, time of onset and degree of reversibility. The health concerns that may be caused by environmental toxicant exposure range in severity from very severe (cancers) to less severe (decreased fertility). Some health concerns may be permanent or irreversible (birth defects, thyroid dysfunction during fetal development), while others affect specific stages of development (precocious puberty). Thus, adverse effects following exposure to potential endocrine toxicants can be defined here as 'diseases or conditions that develop as a consequence of disruption to the endocrine system.'

Probability of Occurrence
The probability, or likelihood, of occurrence of an adverse effect depends on the potency of the toxicant, the susceptibility of the exposed individual, and the level of exposure. Potency is determined by the physical and chemical properties of the toxicant. Endocrine disrupters are believed to interact with hormone receptors, either competing with endogenous hormones for the binding position on the receptor (competitive inhibition) or blocking access to the binding position (noncompetitive inhibition). Environmental toxicants that are able to occupy the binding position on the hormone receptor by virtue of their chemical structure may trigger the cascade of signalling events similar to hormone binding. These toxicants are called 'agonists'. Other toxicants, called 'antagonists', may block this signalling cascade upon receptor binding. As contaminants loosely called 'endocrine disrupters' comprise a myriad of chemical classes, with a wide range of physical and biochemical properties, toxicant potency would have to be determined on an individual basis.

Susceptibility of the exposed individual may be influenced by a variety of factors. Those individuals carrying mutations of the BRCA1 gene, for example, are more susceptible to breast cancer compared to others in the population. It is unknown whether traditional risk factors for cancer (eg. obesity, smoking, genetics) render an individual more susceptible to the development of cancer following toxicant exposure.

The level of exposure depends on the sources from which the toxicant may be released into the environment, the initiating events responsible for its release, and the pathways by which the toxicant may reach human populations. Major sources of potential endocrine disrupting chemicals include industry, food and pesticides. Whether these chemicals are capable of producing adverse effects at environmental concentrations is widely debated. Many studies have investigated adverse effects following accidental exposures at concentrations several times higher than would be normally found in the environment.

Risk Assessment
Risk assessment is "the characterization of the potential adverse health effects of human exposures to environmental hazards". Risk assessment has historically focused on the analysis of chemical, biological and radiological hazards, but has recently expanded to consider the impact of various determinants on the levels of risk experienced by specific populations such as those of lower socio-economic status. Risk assessments are used in conjunction with risk management to develop legislative policy that will protect the public from environmental toxicants shown to be hazardous by the risk assessment.

Risk assessment for environmental toxicants should be developed and carried out by independent experts selected on the basis of their expertise. Risk assessment is a scientific evaluation using a stepwise, systematic approach involving documentation of any constraints, uncertainties or assumptions, which may impact the risk assessment. Risk assessment uses quantitative data in the evaluation of realistic exposure scenarios with consideration of susceptible and high risk population groups. Acute, chronic, cumulative and/or combined adverse health effects should be taken into account in the risk assessment.

Risk assessment consists of four steps: hazard identification, dose-response assessment, exposure assessment and risk characterization.