Consideration of endocrine-related effects in risk assessment
The endocrine system
The endocrine systems (also called hormone systems) of living organisms, including humans, are highly specialized and intricately timed systems that control critical physiological processes. Endocrine systems consist of specialized cells and glands distributed throughout the organism that coordinate both the production of, and the response to, signalling molecules called hormones. The endocrine system of humans and other mammals includes the hypothalamus, pituitary gland, thyroid gland, adrenal glands, ovaries, testes and pancreas.
Processes controlled by endocrine systems include growth and development, reproduction, and responding to environmental cues such as changing temperatures or seasons. Dozens of hormones and hormone classes which are involved in these processes have been identified in both humans and other living organisms. Some of these include:
- Development and functioning of reproductive organs (for example, estrogen and testosterone)
- Regulation of metabolism and nutrient balance (for example, insulin and thyroid hormones)
- Circadian rhythms, hibernation, and insect metamorphosis (for example, melatonin and terpenoids)
- Response to stress and changing environments (for example, cortisol and adrenaline)
Endocrine-related effects of substances
The Canadian Environmental Protection Act, 1999 (CEPA 1999) defines a hormone disrupting substance as a substance having the ability to disrupt the synthesis, secretion, transport, binding, action or elimination of natural hormones in an organism, or its progeny, that are responsible for the maintenance of homeostasis, reproduction, development or behaviour of the organism.
Certain substances (natural or synthetic) can interfere with the normal functioning of endocrine systems. Such effects, referred to as endocrine-related (or hormone-related) effects, can occur when substances mimic natural hormones, prevent hormones from reaching their targets, or change hormone metabolism. In some instances, interference with the normal functioning of the endocrine system can be a mode of action by which substances may cause adverse effects in living organisms. Adverse effects may include delayed or impaired growth, altered intellectual and sexual development, increased susceptibility to certain cancers, disturbances in immune and nervous system function, and lowered ability to reproduce or produce healthy offspring. Various studies indicate that endocrine-active substances may have the most pronounced effects during early developmental periods (such as prenatal and early postnatal development) when hormone-sensitive systems are developing.
Given the fundamental role of hormones in the lifecycle of humans and other living organisms, the biological effects of endocrine-active substances can be of concern. Studies have shown an association between exposure to elevated levels of certain endocrine-active substances and a range of effects, both adverse and non-adverse, in human and other living organisms.
Use of data on endocrine-related effects in risk assessment
Consideration of endocrine-related effects continues to be an important aspect of chemicals management under CEPA 1999, both in prioritizing substances for risk assessment, and in characterizing the hazard of those substances.
Information on endocrine-related effects have been considered in the risk assessments of many substances including: perfluorooctanoic acid (PFOA) and its salts, polybrominated diphenyl ethers (PBDE), hexabromocyclododecane (HBCD), nonylphenol and its ethoxylates, bisphenol A (BPA), and certain flame retardants).
Endocrine-related effects data used in risk assessment can come from standard (in vivo) laboratory toxicity studies using animals. Data can also come from laboratory studies that document effects at the gene and cellular level in a controlled environment such as a test tube, culture dish, or elsewhere outside a living organism (in vitro), from predictive computer models (which are based on chemical structures), and to a lesser extent, from field studies or epidemiological studies that consider exposures and effects to wildlife and humans, respectively. Currently, most internationally-standardized in vivo and in vitro laboratory studies focus on a limited number of endocrine pathways, namely the estrogen, androgen, thyroid, and steroidogenesis pathways. Additionally, adverse effects observed in standard laboratory toxicity studies may also suggest that a substance can have endocrine-related effects.
Standard laboratory toxicity studies primarily provide information on effects that occur at the whole-organism level, and typically include endpoints such as growth and development/maturation, reproduction, carcinogenicity, neurotoxicity, thyroid effects, or changes to blood biochemistry. Effects observed in these types of tests may occur through various modes of action and it is not always known whether these effects are a result of interference with the normal functioning of the endocrine system or some other mode of action such as effects related to cell regulation or development (such as effects on cell membranes or on certain genes). In vitro tests and predictive models can help identify whether endocrine systems may be involved. These types of information are considered within risk assessments carried out under the CMP. However a full understanding of the mode of action is not required in order to take into account potential endocrine effects in a risk assessment.
Risk assessment includes consideration of the effects (including those caused by endocrine-active substances) as well as the potential exposure. For human health, a comparison of the amount of a substance individuals may be exposed to with levels associated with critical health effects is undertaken in order to determine if substances may be harmful at current levels of exposure. The adequacy of the resulting margin of exposure takes into consideration uncertainties in the health effects and exposure databases, including those due to potential endocrine-related effects. In ecological risk assessment, information on endocrine-related effects is one line of evidence that is considered in the overall weight of evidence. Weight of evidence and precaution are applied in both human health and ecological risk assessments.
Research on endocrine-active substances and endocrine-related effects
CEPA 1999, in subsection 44(4), places mandatory obligations on the Minister of Health and the Minister of the Environment with regard to research on hormone disrupting substances.
Health Canada and Environment and Climate Change Canada maintain active scientific research programs that have contributed to advancement internationally regarding endocrine active substances and have contributed to the development of test methods for endocrine disruption through the Organisation for Economic Co-operation and Development (OECD). This research routinely informs risk assessments carried out under CEPA 1999. For a detailed report on activities at Health Canada and Environment and Climate Change Canada related to endocrine-active substances, see the report "Federal research on hormone disrupting substances as required under the Canadian Environmental Protection Act, 1999, Environmental Petition number 340".
Canadian researchers and regulators are actively involved with the international community in the goal to advance and adapt novel approaches in the testing and consideration of endocrine-related effects in risk assessment.
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