An environmental cause of orofacial cleft defects or an unexplained cluster?

The prevalence of orofacial cleft birth defects is approximately 0.5 to 3 per 1000 births worldwide, and rates vary by geographic region, gender, race/ethnicity, and socioeconomic status. Asian and American-Indian populations are reported to have the highest frequency of cleft defects, followed by Caucasian populations and African-Americans. Several potential causal factors have been identified, including genetic syndromes, gene-environment interactions, and prenatal maternal exposures such as medication, alcohol, smoking, occupational and environmental toxins, and in utero nutritional deficiencies. In the current issue of the Southern Medical Journal, Cech et al evaluated the association between low-level radioactivity in drinking water and rates of orofacial cleft defect births among residents of Harris County, Texas. The authors utilized a space-time clustering program and tested for “spatial clusters” geocoded by residential address. Their analysis provides a unique perspective in the evaluation of the potential association between radium and radon levels in drinking water and cleft-birth incidence. Cech and colleagues observed a greater number of cleft defect births than expected, resulting in a significantly increased relative risk of 3.0 (95% CI: 1.8–4.3). The findings reported in this study should be viewed as a valuable “first-step approach” in the evaluation of environmental radioactivity in drinking water and the risk of orofacial defects. Given the methodological aspects of ecologic study design, studies of this nature (eg, environmental contaminant and disease outcome) should be interpreted with caution. Ecologic and aggregate-level studies focus on group comparisons, rather than individual exposure indices. Cech et al, using spatial analyses, identified a “cluster” of 22 cases, compared with 7.3 expected cases. In addition, elevated findings were reported in areas characterized by high levels of radon and radium. While it is possible that radioactivity in drinking water may be associated with orofacial birth defects, other possible factors may explain these findings. As noted by the authors, individual exposure measurements were not performed, as is commonplace in ecologic studies. The lack of individual exposure levels limits the interpretation of the apparent cluster. Another important methodological consideration of any community level study is inand out-migration. The authors noted that in Harris County, urban development began spreading rapidly in the “late 1980s and 1990s,” and between 1991 and 2000, this county “experienced a 20.7% increase in population. ” Cleft births and unaffected live births were identified in Harris County between 1990 and 1994—a period characterized by urban expansion. Thus, it is likely that a proportion of the study population, demarcated by residential location, either migrated into Harris County or transitioned out of the county. Without individual levels of exposure, or a variable indicating time at residence, the actual window of exposure, exposure opportunity, or likelihood of exposure is unknown. Associations for diseases with a short latency period, such as in utero exposures, may be more robust to migratory patterns compared with diseases of long latency periods (eg, most adult cancers). Longterm parental exposures should be considered, however. Cech et al did not evaluate other environmental exposures, that may have confounded the association between radioactivity and orofacial birth defects, such as industrial emissions known to have adverse health effects. For example, ambient air concentrations of environmental pollutants, such as benzene and volatile organic compounds (VOCs), have been identified in the industrial center of Harris County, Texas. Indeed, according to 2003 data, two of the top five urban emitters of benzene in the U.S. are located in Harris County. Moreover, Harris County is home to 10 of the top 100 facilities that report benzene air releases in the Toxic Report Inventory. The association between benzene or other chemical exposures and birth defects is unclear, however. Conley et al measured VOCs at five locations in Harris County and concluded that the atmosphere near the Harris County industrial complex had elevated concentrations of several chemical compounds. Toxic air emissions were detected, albeit at less levels, downwind from emissions sources. Conley and colleagues suggest that VOCs may cause adverse health effects, such as reproductive and endocrine disorders. Because the residents of Harris County, Texas, are likely exposed to numerous chemical agents, isolating a specific exposure (eg, radioactivity in drinking water) and disease response (eg, birth defects) is a challenging undertaking. In summary, the evaluation by Cech and colleagues is a hypothesis generating study, and interpretation should be made in light of potential limitations, such as insufficient individual exposure information, confounding, and potential gene-environment interactions. To formally make an etiologic assessment, future studies should focus on detailed characterization of exposure, in particular, individual exposure measurements, while accounting for potential confounders, such as genetic syndromes, race, socioeconomic status, nutrition, maternal age and prenatal exposures. As noted by the From Exponent Inc.,Wood Dale, IL.