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REPRODUCTIVE AND DEVELOPMENTAL TOXICITY ASSOCIATED WITH DISINFECTION BY-PRODUCTS OF DRINKING WATER
Citation:
Klinefelter, G R., E S. Hunter III, AND M G. Narotsky. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY ASSOCIATED WITH DISINFECTION BY-PRODUCTS OF DRINKING WATER. Presented at 2nd International Conference on Safety of Water Disinfection: Balancing Chemical & Microbial Risks, Miami, FL, November 15-17, 1999.
Description:
Over the past decade many toxicologic studies have addressed the potential for disinfection byproducts of drinking water to elicit alterations on the reproductive system and fetal development.
The types and designs of these studies vary considerably, but in general they can be classified as: screens to evaluate fetal development, whole embryo culture assessments, short-term screens of the adult male and female (pregnant and nonpregnant) reproductive system, and assessments of developmental reproductive effects. Of the chemical classes of disinfection byproducts known to exist, the trihalomethanes and the haloacetic acids have been the focus of much of the reproductive and developmental toxicology assessments. This is due both to the fact that these classes represent the most prevalent disinfection byproducts in drinking water, as well as to the fact that these disinfection byproducts do indeed produce significant alterations in reproduction and development at experimental, i.e. effect-finding, exposures.
Alterations in fetal development are common to both chemical classes and are characterized by decreased pup viability associated with cardiac defects, neural tube defects, and other craniofacial anomalies. While the trihalomethanes do not produce a profile of reproductive effects, the haloacetic acids, particular the di- substituted haloacids, produce profound effects on the adult male reproductive system. Alterations that are common to the disubstituted haloacid, i.e. dibromo-, dichloro-, and bromochloro-acetic acids include delays in spermiation, formation of atypical residual bodies, as well as fused sperm and malformed spermatids. Recent studies have established diminutions in specific sperm proteins (e.g. SP22) and compromised fertility at doses as low as 8 mg/kg. Both fetal development and reproductive function are more easily perturbed by the brominated species than the chlorinated species.
The use of in vitro models to study developmental and reproductive tissues allows the investigator to address questions about the direct effects of a xenobiotic on the cultured tissue. It is clear that in vitro exposure to the haloacetates alters craniofacial and early heart development as observed in vivo. Moreover, direct in vitro exposure of embryos provides an excellent opportunity to determine structure-activity relationships, study mixture additivity, and explore putative mechanisms of action. Similarly, the isolated seminiferous tubule cultures provide structure-activity and mechanistic data. Diminutions in the synthesis of specific proteins has now been observed following both in vivo and in vitro exposures to dibromoacetic acid. It remains to be determined how these proteins relate to the disruption of spermatogenesis observed in vivo.
The reported association between trihalomethane levels in drinking water and the occurrence of spontaneous abortion has fueled significant interest in the toxicological correlate. In this regard, full litter losses have been reported following gestational exposure to bromodichloromethane, and in particular, when exposure occurs during the LH-dependent period of pregnancy maintenance. Since LH maintains pregnancy in all mammals, the correlate may exist.
Data regarding the potential for disinfection by-products to alter the developing reproductive system, (i.e. gonadal differentiation, puberty) are crucial to fully address the potential reproductive effects attributed to disinfection by-products of drinking water. It remains to be determined whether the reproductive effects observed following adult exposures will be manifest at lower exposure levels when exposure occurs during periods of reproductive development, or whether a new profile of effects will be established. Recently, studies in our laboratory have been conducted to examine pubertal development following gestational or lactational exposures to dibromoacetic acid. While preliminary, the data strongly suggest that drinking water exposure from gestation day 15 onward results in significant delays in puberty in both male and female rats. Regardless of the mechanism underlying this pubertal delays, the data strongly suggest that the haloacetic acids may represent a class of endocrine-disruptive chemicals.
In light of all of observed developmental and reproductive effects it is indeed comforting to know that human exposure estimates based on experimental NOAELs are approximately 10,000 times greater than the 95percentile occurrence level of these disinfection byproducts. However, while these margins of exposure suggest no relevant risk to human reproduction and development, this comfort should be tempered with caution as there is still no multigenerational study on a single disinfection byproduct, and disinfection byproducts exist as complex mixtures; multigenerational studies on mixtures are now merely visions.