It's time to rethink dose: the case for combining cancer and birth and developmental defects.

VOLUME 109 | NUMBER 6 | June 2001 • Environmental Health Perspectives Toxicology, literally the scientific study of poisons, is a descriptive and experimental science that details the biological consequences of exposures to toxicants. The dose makes the poison—so goes the oftrepeated observation of the 16th-century progenitor of modern pharmacology, Theophrastus Paracelsus. Over the past three decades a growing number of in vitro and in vivo studies shows that this widely accepted assertion has important variants and exceptions. Dose surely affects the toxicity of any substance, whether water, foods, or metals. However, it is increasingly evident that in determining the biological importance of any given exposure, the period of development (or the critical window during which exposure occurs) and the rate at which a dose is absorbed can be even more important than the total quantity of exposure. Although birth defects, developmental defects, and cancers in children and infants remain rare, they sometimes fall into “clusters” and unfortunately remain largely unexplained. However, a spate of recent experimental and epidemiologic findings makes clear the exquisite sensitivity of prenatal and postnatal periods. Therefore, it is time for a new paradigm that takes into account the fact that some cancers and some birth and developmental defects stem from common exposures that occur early in life. Such a paradigm will improve the power of studies by combining the assessment of health end points that are likely to arise from exposures that take place during critical windows of development. In addition, such a paradigm will also challenge epidemiologic investigation of chronic diseases, for which early windows of vulnerability and long latencies are involved. For chronic diseases such as cancer and neurodegenerative disorders, it does not make biological sense to assess solely contemporaneous measures of exposure. Like most cancers in children, neuroblastoma, the most common cancer in children under 1 year of age, is believed to arise as a terminal cell differentiation, reflecting prenatal influences or germ cell mutations. In a recent review of 95% of all children in the United States diagnosed with neuroblastoma (from trial groups of the Pediatric Oncology Group and the Children’s Cancer Group) Daniels et al. (1) found that pesticide use in both home and garden significantly increased the odds ratios (ORs), 1.6 and 1.7, respectively. A stronger OR of 2.2 was found in children who were diagnosed after 1 year of age. They believe that the stronger effect in older children may arise from either greater cumulative exposures or differential effects of pesticides in an etiologic pathway marked by an older age at diagnosis (1). Interestingly, there was no evidence that MYCN gene status modified the risk of pesticides for neuroblastoma. Daniels et al. (1) speculated that some widely used pesticides, such as chlorpyrifos, chlordane, and lindane, affected the immune system by decreasing regulation of cell proliferation or surveillance for dysfunctional or undifferentiated neural crest cells. This finding is even more remarkable because recent monitoring information indicates that these materials are ubiquitous in the United States. Because of this widespread exposure, any epidemiologic study will be biased toward the null hypothesis (2,3). This study on neuroblastoma parallels findings in farm families in Norway, where children residing on farms around the time of birth had an OR of 2.5 for the same type of tumor (4). Paternal exposures of interest include those acting on the father’s maturing germ cells in the 3 months before conception. In addition, central nervous system defects, such as spina bifida and hydrocephaly, and cancer were also associated with paternal use of pesticide spraying equipment. There is growing evidence that some cases of testicular cancer in younger men and breast cancer in younger women may arise from prenatal or early childhood exposures. Some studies have found that both maternal and paternal exposures can affect the risk of testicular cancer. For instance, ORs of testicular cancer were increased more than 4-fold for young men with mothers working in health-related occupations and fathers working in automobile service stations (5). With respect to paternal exposures alone, several studies have provided evidence that male-mediated exposures can critically affect the risk of childhood cancer. Thus, in a cohort study based on a population of 235,635 children in Sweden, Feychting et al. (6) followed children from birth to 14 years of age and found increased risk of nervous system tumors related to paternal occupational exposure to pesticides [relative risk (RR) = 2.36; 95% confidence interval (CI), 1.27–4.39] and work as a painter (RR = 3.65; 95% CI, 1.71–7.80), and an increased risk of leukemia related to wood working by fathers (RR = 2.18; 95% CI, 1.26–3.78). In other studies, paternal exposure to solvents, cutting oils, paints, dusts, and fumes has been found to be associated with an increased risk of testicular cancer and leukemia in these men’s children. For example, in one study of rare childhood malignant germ-cell tumors, fathers of cases were more likely than fathers of controls to have been exposed to solvents, plastic or resin fumes, metals, and cleaning compounds (5,7). Animal studies of the sensitivity of the developing organism have repeatedly confirmed that susceptibility depends on the rate of ongoing cell division at the time of exposure. The synthetic estrogen diethylstilbestrol (DES) produces structural defects in the seminiferous tubule of male offspring after maternal exposures during critical phases of organogenesis (8). A single dose of 17β-estradiol early in gestation can create defects that do not occur with exposure later in pregnancy or with neonatal exposure (9). Moreover, early gestational exposure to 17α-estradiol, normally considered a very weak estrogen, induces defects in offspring, whereas exposure to the same It’s Time to Rethink Dose: The Case for Combining Cancer and Birth and Developmental Defects PERSPECTIVES Editorial