Authors
Mocarelli, P., Gerthoux, P.M., Ferrari, E., Patterson, D.G., Kieszak, S.M., Brambilla, P., Vincoli, N., Signorini, S., Tramacere, P., Carreri, V., Sampson, E.J., Turner, W.E.

Title:
Paternal concentrations of dioxin and sex ratio of offspring

Source:
The Lancet 355:1858-1863, 2000.

Summary:
Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) occurred during an explosion in a herbicide manufacturing plant in Seveso, Italy in 1976. TCDD is a persistent contaminant and a known endocrine disrupter. Previous research has suggested that an association exists between a population's exposure to TCDD and a lower male/female sex ratio in their offspring. This retrospective cohort study was conducted to explore the association between exposure to TCDD in Seveso, Italy as measured by serum samples and the sex ratio of the offspring of the exposed population. The effect of the parents' sex and/or age at the time of the exposure was of particular interest.

The study population consisted of people who lived in the area surrounding Seveso, Italy at the time of the explosion, and who had sired a child born between April 1, 1977 and Dec 31, 1996. Exposure was determined by analyzing TCDD concentrations in stored serum samples from people living in the exposed areas surrounding Seveso at the time of the explosion. These samples were taken between 1976 and 1977 for the purpose laboratory tests, and were offered free of charge to people in living in the exposed areas. The samples provided an indication of the TCDD concentration in the blood shortly after exposure. In total, serum samples from 239 men and 296 women were used. Birth data about their offspring was obtained from the municipal censes. The exposed population was defined as parents where one or both partners had lived in identified contaminated areas at the time of the explosion and had TCDD serum levels greater than 15ppt. The unexposed population was defined as people living outside the contaminated zone at the time of the explosion or those living within the contaminated zone but had TCDD serum levels equal to or less than 15ppt.

In total, the exposed population gave birth to 346 girls and 328 boys. Overall, the sex ratio of the offspring was not significantly different from the expected. However, evaluation of the data by parental exposure status found significant associations. The sex of the exposed parent was an important factor in predicting the sex ratio of the offspring. The sex ratio was significantly different from the expected (0.514) when the father was categorized as exposed, but not significantly different when either both parents were considered 'unexposed' or only the mother was 'exposed'. Increasing TCDD concentrations in the father were associated with a significant increase in female births. This effect was observed at concentrations of less than 20 ng per kg bodyweight. Age at exposure was also found to be important. Fathers that were less than 19 years of age at the time of exposure were significantly more likely to father girls than boys (sex ratio 0.38, 95% confidence interval 0.30-0.47). This suggests that the effects of exposure to TCDD may persist for years.

This study was well designed and used strong methodology and analysis. A considerable strength was the use of a laboratory test to determine exposure, this eliminates the uncertainties associated with recall bias commonly associated with exposures assessed using survey data or estimating exposures.

External data presented in the discussion of this study illustrates that an increase in female births was already occurring in the years preceding the explosion (1973-1976); a sex ratio consistent with the 'expected' was observed between 1966 and 1972. As serum data was not available from these time periods it is unclear whether the change in sex ration was in fact due to the TCDD contamination. The findings presented in this study may not be directly generalized to the population at large. The study population was exposed to high levels of TCDD, and detected effects at concentrations of less than 20 ng per kg bodyweight or 20 ppt. However the literature suggests that much lower levels are observed in the population at large. For example one study found mean serum TCDD concentration in a population of pesticide sprayers (more highly exposed than the general population) to be between 2.6 and 8.1 ppt (Johnson et al 2001). Other studies, based on adipose tissue lipid levels (which are comparable to serum concentrations for TCDD) found that the body burden of TCDD in the general population is currently about 2 ppt and made the prediction the these levels were likely to decrease further over the next 15 years, to between 0.5 and 1 ppt (Aylward et al 2002).

Nevertheless, this study provides important information in understanding the potential effects of paternal exposure to TCDD on the sex ratio of the population, and is an important contribution to the literature.

References:
Johnson E, Shorter C, Bestervelt L, Patterson D, Needham L, Piper W, Lucier G, Nolan C. (2001)
Serum hormone levels in humans with low serum concentrations of 2,3,7,8-TCDD. Toxicol Ind Health. May;17(4):105-12.

Aylward LL, Hays SM. (2002), Temporal trends in human TCDD body burden: Decreases over three decades and implications for expo