A Practical Approach, Second Edition=Ronald D. Ho.pdf

860 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONExposures that affect the female reproductive system are also important with respect to thestage of reproductive life or different physiological states (e.g., nonpregnant, pregnant, lactating,perimenopausal, postmenopausal). Exposure of pregnant women to diethylstilbestrol (DES) at atime when critical stages of reproductive system development were occurring resulted in a numberof cases of reproductive tract abnormalities and a rare form of cancer in young women exposed inutero. 140,141 Compounds that cause destruction of primordial follicles or primary oocytes or thatincrease the rate of apoptosis in the germ cells may result in infertility or alter time to pregnancy,disrupt follicular recruitment, ovulation, and ovum transport, and lead to changes in viability orfertilizability of the egg.Children and adults are exposed directly to contaminants via water, food, air, and soil. Dustand paint or anything that can be mouthed by a young child should also be considered a potentialsource of exposure. The period and duration of exposure should be related to life stage of developmentor reproduction. For example, exposures should be characterized as preconception, first,second, or third trimester of pregnancy (or more specific periods, if possible), infancy, early, middle,and late childhood (specific ages, if possible), adolescence (stage of puberty and development),adulthood (by age), pre- or postmenopausal, older adult, and the aged. These life stages may havedifferent sensitivities to an agent, and exposure estimates should be characterized for as many aspossible. In addition, exposure to either parent prior to conception should be considered as apossibility in the production of adverse developmental effects. 142–144Exposures that can cause developmental and reproductive toxicity may be for short or longdurations. Many experimental studies have confirmed for a number of agents that a single exposureis sufficient to cause developmental or reproductive toxicity, depending on the life stage, i.e.,repeated exposure is not a necessary prerequisite for adverse outcomes. Thus, agents with shorthalf-lives, as well as those that show accumulation with repeated exposures or that have long halflives,may cause effects. The pattern of exposure, whether intermittent or continuous, as well aspeak exposures and average exposure levels over the period of exposure, should be examined.Exposures affecting development and reproduction will often result in latent effects. For example,effects of exposure during pregnancy may not be manifest until after birth in the form ofstructural malformations, growth retardation, cancer, or mental retardation or other functionaldefects. Likewise, effects of exposures that enhance follicular degeneration early in developmentmay not become apparent until an early onset of menopause is noted. Other types of effects thatmay not become apparent until long after exposure during early life stages include cancer, heartdisease, neurodegenerative disease, and shortened lifespan.4. Risk CharacterizationRisk characterization is the final step in the risk assessment process and involves integration of thehazard characterization and dose-response assessment with the exposure assessment. Integral torisk characterization is information on the quality of the data for the hazard evaluation and theexposure assessment, relevancy to humans, strengths and weaknesses of the database, assumptionsmade, scientific judgments, and the level of confidence in determining potential risks to humans.All of these factors are part of the weight-of-evidence determination. Table 21.4 gives a list ofissues to be considered in each of the components of risk assessment and can serve as a guide forthe questions to be addressed in risk characterization.The weight-of-evidence information is communicated to the risk manager along with thequantitative information on the range of effective exposure levels, dose-response modeling estimates(e.g., the BMD and BMDL), appropriate uncertainty factors for each duration reference value, aswell as the reference values. Information on developmental and reproductive toxicity is consideredan important part of the database used in calculating chronic RfDs and RfCs and must be weighedappropriately relative to other adverse outcomes. When developmental and reproductive toxicity© 2006 by Taylor & Francis Group, LLC