Paolo Mocarelli, Pier Mario Gerthoux, Enrica Ferrari, Donald G Patterson Jr, Stephanie M Kieszak, Paolo Brambilla, Nicoletta Vincoli, Stefano Signorini, Pierluigi Tramacere, Vittorio Carreri, Eric J Sampson, Wayman E Turner, Larry L Needham Department of Laboratory Medicine, University Milano-Bicocca, Hospital of Desio, 20033 Via Benefattori 2, Desio-Milano, Italy (Prof P Mocarelli MD, P M Gerthoux PhD, E Ferrari PhD, P Brambilla MD, N Vincoli PhD, S Signorini MD, P Tramacere MD); Division of Laboratory Sciences (D G Patterson PhD, E J Sampson PhD, W E Turner MS, L L Needham PhD); and Division of Environmental Hazards and Health Effects (S M Kieszak MA), National Center for Environmental Health, Centres for Disease Control and Prevention, Atlanta, GA, USA; and Department for Preventive Medicine, Ministry of Health, Region Lombardia, Milano, Italy (V Carreri MD)

SUMMARY Background:

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin), is commonly considered the most toxic man-made substance. We have previously shown that high serum concentrations of TCDD in parents from Seveso, Italy, were linked to their having a relative increase in the number of female births after the parents exposure to a release of dioxin in 1976. We have continued the study to determine whether the parents’ sex and/or age at exposure affected the sex ratio of their children.

Methods We measured the TCDD concentrations in serum samples from potentially exposed parents collected in 1976 and 1977, and investigated the sex ratio of their offspring.

Findings:

Serum samples were collected from 239 men and 296 women. 346 girls and 328 boys were born to potentially exposed parents between 1977 and 1996, showing an increased probability of female births (lower sex ratio) with increasing TCDD concentrations in the serum samples from the fathers (p=0·008). This effect starts at concentrations less than 20 ng per kg bodyweight. Fathers exposed when they were younger than 19 years of age sired significantly more girls than boys (sex ratio 0·38 [95% CI 0·30-0·47]).

Interpretation:

Exposure of men to TCDD is linked to a lowered male/female sex ratio in their offspring, which may persist for years after exposure. The median concentration of dioxin in fathers in this study is similar to doses that induce epididymal impairments in rats and is about 20 times the estimated average concentration of TCDD currently found in human beings in industrialised countries. These observations could have important public-health implications.

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The Lancet Press Release
Issue 27 May, 2000 Embargoed 18:30h (Eastern time) 25 May, 2000

Dioxin exposure linked to long-term decrease in male births

(pp 1838,1858,1883)

A reduction in the proportion of male births remains the long-term effect of exposure to the toxic pollutant dioxin, nearly a quarter of a century after industrial explosion in northern Italy, according to research published in this week’s issue of THE LANCET.

The industrial by-product dioxin is commonly considered the most toxic man-made substance. Previous research has shown that high serum concentrations of dioxin in parents from Seveso, Italy were linked to their having a relative increase in the number of female births after the parents exposure to al release of dioxin in 1976.

Paolo Mocarelli and colleagues from Desio Hospital University Bricocca, Milan, Italy continued the study to find the effect of serum dioxin concentrations of dioxin on the sex ration of offspring in the Seveso population: they also aimed to determine whether the parents’ age at exposure affected the sex ratio of their children. Dioxin concentrations were measured in serum samples from exposed parent collected in 1976 and 1977, and the sex ratio of their offspring was investigated.  Samples were collected from 239 men and 296 women. 346 girls and 328 boys were born to exposed parents between 1977 and 1996, showing an increased probability of female births with increasing dioxin concentrations in the serum samples from the fathers. This effect started at concentrations less than 20 ng per kg bodyweight. The study showed that fathers exposed when they were younger than 19 years of age sired significantly more girls than boys (sex ratio of male: female births 0.382 compared to the world wide average of 0.514).

The investigators conclude that exposure of men to dioxin is linked to a lowered sex ratio which may be persist for years after exposure. The average concentration of dioxin in fathers in this study is similar to doses that induce reproductive impairments in rats, and is about 20 times the estimate average concentration of dioxin currently found in humans beings in industrialised countries.

Paolo Mocarelli comments: "Dioxin contamination is a world wide problem.   These data will assist health authorities to better define risk assessment for these toxic molecules. In fact the lowering sex ratio in human has been directly linked for the first time to male exposure to an environmental pollutant and at its relatively low doses. This effect can be tentatively interpreted as a result of dioxin endocrine disruption of the male reproductive system." (Quote by e-mail; does not appear in published paper).  In an accompanying Commentary (P 1838), Richard Clapp and David Ozonoff from Boston University School of Public Health, USA, comment that how dioxin reduces the number of sons in the Seveso study is unclear. They add that ‘it is a public health maxim that males have shorter life expectancies than females at every age from conception onward. On this basis, if in-utero exposures are toxic to both sexes, one might expect greater fetal loss in males. Whatever the mechanism, the Seveso finding is of public-health interest since it was seen at the exposure levels that are lower than those associated with many of the other effects of dioxin’.

Two research letters (p 1883) published in this week’s issue of THE LANCET also concern dioxin contamination. The first, by Manfred Neuberger and colleagues reports how Austria " unlike other European countries " has recently introduced a policy to prevent human exposure to dioxin by restricting levels entering the animal feed of chickens and pigs. In the second research letter, H Kiviranta and colleagues showed that dioxin concentrations in a population that frequently eat fish from heavily polluted Baltic Sea are comparable to those seen in inhabitants of Seveso, Italy (described above).

Contact: Professor Paolo Mocarelli, University Department of Clinical Pathology, Hospital of Desio, Piazza Benefattori 1, 20033 Desio, Milano, Italy; T) 39 03 62 3832 96) M ) +39 (0)347 278 6198; F) 3903 62 383464, E) mocarelli@uds.unimib.it

 Dr. Richard Clapp, Department of Environmental Health, Boston University School of Public Health, Boston MA 02118, USA; T) + 1 617 638 4640; F) 1 617 638 4857; E) dozonoff@bu.edu

 Dr Manfred Neuberger, Univerity of Vienna, Institute of Environmental Health , Department of Prventive Medicine, Kinderspitalgasse 15, A-1095 Wien Austria; T) +43 1 4277 64710: F) 43 1 4277 64799; E)