Risk assessment of chemicals: What about children?

Autor: Wolterink G, Piersma AH, Engelen JGM van, CSR, LEO
Jazyk: angličtina
Rok vydání: 2007
Předmět:
Popis: In regulatory toxicology there is increased awareness and concern that children and adults may differ in their susceptibility to xenobiotics. In this report a concise overview of the relevant data on the differences between adults and children with respect to the kinetics, dynamics and exposure to chemicals is presented and adequacy of currently used toxicological tests for regulatory purposes is discussed. In view of the potentially increased vulnerability of children a number of recommendations for further development of risk assessment of chemicals are made. There are three major areas in which children and adults differ: exposure to and toxicokinetics and toxicodynamics of xenobiotics. Especially the situation in which children are higher exposed than adults this needs full attention. Children consume more food and drink more fluids per kg body weight than adults, and their dietary pattern is different and less varied. Moreover, children have a relatively high inhalatory rate (which may lead to a higher inhalatory exposure) and a high body surface-body weight ratio (which may result in a higher dermal exposure). Children may also be more exposed to toxic substances than adults since children spend more time in the same room or area, are in closer contact with a contaminated surface (e.g. by crawling) and display less hygienic behaviour (mouthing of hands, objects, surfaces; pica behaviour). The route of exposure may be of importance for the potentially toxic effects of a chemical. In most toxicological studies for regulatory purposes the oral route of administration is used. However, the expected route of exposure of a child should be taken into consideration in the design of toxicological studies since the systemic exposure to a chemical may differ due to different levels of absorption and the absence of a first pass effect following dermal and inhalatory absorption. A further point of concern, for adults as well as children, is the aggregate exposure to a specific chemical from different sources and the cumulative exposure to different substances with the same mechanism of action (e.g. organophosphates and carbamates). The physiological differences between children and adults may affect the kinetics of a substance in the body, which may render the child less or more susceptible to toxic effects of a chemical. For instance, oral absorption of a substance may be affected by the different gastric pH, gastric emptying rate, concentration of digestive enzymes and gut flora. The high respiratory activity and higher body surface-body weight ratio may increase the relative inhalatory and dermal absorption of substances. The high body water content, the low plasma protein binding capacity and the permeability of the blood brain barrier may affect the distribution of a chemical. The immaturity of the metabolic enzymes in the liver and the low renal blood flow and glomerular filtration rate may affect the elimination of a xenobiotic. With respect to toxicodynamics, i.e. the interaction between a chemical and the body (organs, tissues) a major concern is the influence that a chemical may exert on the developing organs and systems in young children. Disruption of proliferation, differentiation, migration and maturation of cells may have severe and irreversible consequenses. In humans, the development of certain organs or systems, e.g. the respiratory tract, the immune and endocrine systems and the brain, continues long after birth. The presently used reproduction toxicity tests and the newly introduced neurodevelopmental toxicity test mainly focus on reproductive and neurotoxic effects and are not designed to detect, for instance, immunotoxic effects, effects on lung development or general effects on histopathology or haematology. It is recommended that it is ascertained that, in case of exposure through the milk of the dams, significant quantities of test substance are excreted in the milk. Moreover, since the critical windows in the development of laboratory animals and children are not necessarily the same, the exposure period should be carefully examined. Since there is a multitude of processes that may differ between children and adults, and the net result of these differences is not clear, at present there is not sufficient information to give a general quantitative statement with respect to differences in vulnerability. For instance, an increased absorption of a substance in a child does not necessarily lead to an increased risk if there is no formation of a toxic metabolite or if there is an increased elimination of the substance. It should be noted that in risk assessment, the use of an intraspecies factor of 10 implies that the 'most sensitive child' is about 10x more sensitive than the 'average' human, and thus that there is a 100-fold variation in susceptibility in the entire human population. In addition, the use of the default assessment factor of 10 for interspecies extrapolation implies that the average human is 10 times more sensitive than the most sensitive animal tested. In general, if a full set of toxicological data is available, the presently used assessment factors (10 x 10) are considered adequate in safeguarding the human population. However, the use of an additional assessment factor in order to protect the sensitive groups in the human population, among others children, should always be considered, on a case-by-case basis. For future developments in risk assessment of chemicals with respect to children a number of recommendations are made. For adults as well as children more insight into the specific exposure scenarios is needed. It is proposed to design a decision tree which indicates whether a toxicological data set and the knowledge on the specific exposure are adequate for risk assessment for children. The suitability of young animal toxicity tests should be investigated. A comparison of the dose-response data and the NOAELs of tests in adults and juveniles may provide insight in the range of intraspecies variation with respect to age. Since for pharmaceuticals human data are available it will be worthwhile to follow the developments in the field of kinetics and dynamics of paediatric pharmaceuticals. By using distributions of the physiological and kinetic parameters and PBPK modeling it can be assessed which group of children is most at risk for a certain chemical.
Databáze: OpenAIRE
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