Assessment of environmental chemicals affecting puberty the signaling pathway for leptin in the devel- opment of puberty is not known, and further work is necessary to define this mechanism and the difference in leptin levels among racial/ethnicity groups (Danadian et al. 1999; Ruhl et al. 2004). The early onset of puberty is clinically and socially important to the population. The early onset of thelarche is associated with an early diagnosis of breast cancer in susceptible popu- lations (Hamilton and Mack 2003) and adult obesity (Biro et al. 2003). Breast cancer is asso- ciated with an early age of onset of menarche as well. Girls attaining menarche after 13 years of age were observed to have a one-third decreased risk [multivariate relative risk = 0.66; 95% conﬁdence interval (CI), 0.44–0.99] for breast cancer compared with those attaining menarche at a younger age (Garland et al. 1998). This effect also was characterized by deﬁning a 2-year delay in the age of menarche to a 10% decrease in risk for breast cancer (Hsieh et al. 1990). These observations imply the need for additional surveillance for these measures because they can affect diagnostic evaluation (Chalumeau et al. 2002; Dorn et al. 1999; Kaplowitz and Oberfield 1999). The social consequence is that children will need to learn how to adapt to their maturing bodies at an earlier age, and our public school system will need to re-evaluate the timing and struc- ture of health education classes because the early onset of puberty has been associated with risky and unhealthy behaviors (Orr and Ingersoll 1995; Simon et al. 2003). Environmental Chemicals Several environmental chemicals are known to have hormonal activity, and their effects are well demonstrated in animal studies (Goldman et al. 2000; Stoker et al. 2000). The hormonal effects of these chemicals can be categorized by estrogenic, antiestrogenic, androgenic, antiandrogenic, and thyroidal activities. Depending on a chemical’s hor- monal activity, onset of puberty may be either delayed or accelerated. There is also experi- mental evidence demonstrating that chemical exposures during gestation can result in altered mammary gland development (Nikaido et al. 2004; Rayner et al. 2004) and age of pubertal onset (Casanova et al. 1999; Nikaido et al. 2004; Tou et al. 1998). The effects of these chemicals on the growth, development, and reproductive health of people are largely unknown because this remains a relatively new area of investigation. The chemical class that is best described in this area is polychlorinated biphenyls (PCBs). PCBs and their hydroxy- lated metabolites are known for their effects on the thyroid regulatory pathway, which can affect neurodevelopment (Jacobson and Jacobson 1996; Meerts et al. 2002). In addi- tion to PCBs, several other chemicals with hormonal activity are associated with health effects after exposure, some of which are dis- cussed below (Table 1). (Note that the discus- sion of these chemicals does not imply that the NCS has determined that these chemicals either cause these health effects or will be included in the NCS.) Environmental lead was recently observed to be associated with delayed age of onset of puberty in girls in the United States (Selevan et al. 2003; Wu et al. 2003). In a cross- sectional survey of 1,706 girls 8 through 16 years of age during 1988 through 1994, increased blood lead level was associated with a decreased likelihood for the attainment of either pubarche or menarche but not thelarche (Wu et al. 2003). Girls with lead levels in the ranges of 2.1–4.9 and 5–21.7 µg/dL were approximately 50 and 80%, respectively, less likely to reach these measures of puberty than those with lead levels between 0.7 and 2.0 µg/dL. In younger girls (8 through 12 years of age), the percentage of girls attaining pub- arche by age decreased with increasing blood lead levels. When the same population was analyzed by racial/ethnicity groups, a higher blood lead level (3 vs. 1 µg/dL) in African- American girls was associated with delayed onset of pubarche, thelarche, and menarche by 2–4 months (Selevan et al. 2003). There also was a decreased likelihood of approximately 60% for the attainment of a successive Tanner stage for breast and pubic hair development in African-American girls. Similar delays in the- larche and pubarche were observed in Mexican-American girls, except the delays were smaller in magnitude. No differences in blood lead levels were observed in pubertal outcomes in non-Hispanic white girls. Underlying differ- ences in growth or hormonal regulation among the racial/ethnic groups may explain the observed pubertal effects in association with lead exposure (Wong et al. 1998). Chronic exposure to lead was demon- strated to affect the hypothalamo–pituitary– gonadal axis by altering serum levels of gonadotropic and androgenic hormones. In occupationally exposed males, prolonged lead exposure at the workplace was associated with decreased serum testosterone (Rodamilans et al. 1988). Serum luteinizing hormone levels were found to be lower both in occupa- tional males (McGregor and Mason 1990) and in children 11 through 13 years of age from the general population (Vivoli et al. 1993) with high lead levels. The effects of exposure to environmental lead on the levels of estrogens, androgens, and gonadotropins in younger children and their pubertal develop- ment remain to be determined. Future studies in this area need to pay particular attention to the timing of exposure during develop- ment and the contribution of race/ethnicity to such ﬁndings. Environmental Health Perspectives • VOLUME 113 | NUMBER 8 | August 2005 The effects of the exposure to persistent organohalogen chemicals on maturation have been evaluated in several epidemiologic investi- gations. Two studies evaluated the contribu- tion of in utero and postnatal exposure to these chemicals. Polybrominated biphenyls (PBBs) were found to be associated with premature thelarche in girls who were breast-fed by moth- ers with high serum PBB levels (≥ 7 µg/L) resulting from exposure to milk from cows given contaminated feed (Blanck et al. 2000). However, in girls who were not breast-fed by their PBB-exposed mothers, the maternal serum PBB level was not associated with early breast development, thus suggesting the contri- bution of postnatal exposure to altered pubertal development in this setting. There also was an increased risk (adjusted hazard ratio, 3.70; 95% CI, 1.41–9.71) for the earlier onset of menar- che in girls breast-fed by mothers with high serum PBB levels compared with girls who were not breast-fed by mothers with low serum PBB levels (less than or equal to limit of detec- tion). In the North Carolina Infant Feeding Study (1978 through 1982), in utero exposure to either PCBs or 1,1´-(2,2-dichloroethenyli- dene)-bis[4-chlorobenzene] [p,p´-DDE, a metabolite of dichlorodiphenyltrichloroethane (p,p´-DDT)] was not associated with the time to attainment of the Tanner stages in boys and girls (Gladen et al. 2000). However, increasing human milk levels of PCBs and p,p´-DDE were associated with increased body weight in girls and boys, respectively. Other studies evalu- ating the effects of exposure to PCBs and dioxin-like compounds (Den Hond et al. 2002) and to endosulfan (Saiyed et al. 2003) on the timing of pubertal milestones found either no effects or delayed effects, which var- ied by gender. These latter reports were limited by either the contribution of potential risk fac- tors (e.g., congenital disorders) to the ﬁndings or their inability to relate their ﬁndings to pre- natal versus postnatal exposure because the par- ticipants were evaluated only during puberty. Finally, nonpersistent chemicals such as phthalates (Colon et al. 2000) and phyto- estrogens have been investigated for their association with altered time of onset of puberty as well. Phytoestrogens are naturally occurring environmental chemicals found in fruits, vegetables, and legumes (e.g., soybeans) and have notable estrogenic activity. In a case–control study, the intake of soy-based formula was associated with an increased like- lihood of premature thelarche in children younger than 2 years but not in children diag- nosed with thelarche beyond this age (Freni- Titulaer et al. 1986). This suggests that various factors were most likely contributing to early breast development in this study population, depending upon the age of onset of the disorder. In both these areas of investi- gation, additional work is needed to clarify 1101