Anogenital Distance: Defining "Normal"
Referencing: Validity of Anogenital Distance as a Marker of in Utero Phthalate Exposure and Authors' Response
In their letter to EHP, McEwen and Renner (2006) dismissed the findings of Swan et al. (2005), who reported a significant relationship between a measure of anogenital distance (AGD) in boys and levels of phthalate metabolites in their mothers' urine during pregnancy. AGD is a sexually dimorphic index that, on average, is twice as great in males as in females, so it serves as a marker of proper male development. McEwen and Renner based their argument on an idiosyncratic form of logic. They asserted that
All male infants evaluated in the study appeared normal . . . there is no evidence for potential adverse effect in the test population. . . . no conclusion can be drawn whether the reported values are normal or abnormal. The range of AGD values . . . likely represents typical biologic variation that would be expected to occur among normal study subjects.
McEwen and Renner seem to be wholly unfamiliar with the meaning of a modest or even a slight shift in the mean of an index that reflects the distribution of susceptibility in a population. I have pointed out (Weiss 1988) that even a 5-point (5%) reduction in mean IQ (intelligence quotent) in a population of 100 million increases the number of individuals classified as retarded from 6 million to 9.4 million. It is this kind of relationship that eventually prompted the Centers for Disease Control and Prevention (CDC) to lower its definition of elevated lead risk levels in blood, set at 40 µg/dL in 1970, to 10 µg/dL in 1991 (CDC 1991). Bellinger (2006) put it this way:
A small change in the mean signals predictable accompanying changes in the proportions of individuals in the source population who fall into the tails of the distribution, where individuals who meet diagnostic criteria are found. Thus, the importance of a shift in group mean lies not in what it indicates about the average change among members of the study sample, but what it implies about the changes in the tails of the distribution in the population from which the study sample was drawn.
He noted, based on Rose (1981), that in a population with a prevalence of clinically defined hypertension of 15%, a 5-mm reduction in mean systolic blood pressure would result in a 33% decrease in prevalence (Bellinger 2006). Epidemiologists recognize that a slight decrease in mean blood pressure in a population is translated into a major decrease in the incidence of serious cardiovascular events such as heart attacks.
We already know that shortened AGD at birth is one element, the leading edge, as it were, of the "phthalate syndrome" in rats, which is marked by testicular pathology, reduced spermatogenesis, hypospadias, and cryptorchidism, a compilation of signs indicating disordered male development that Sharpe (2001) and others have noted to be on the increase in industrialized nations. An almost imperceptible shift to a lower mean AGD in the human male would foreshadow a heightened prevalence of reproductive system dysfunction. Is that the connection now emerging in the clinic?
If McEwen and Renner's (2006) criteria for "normal" were to govern the way in which we define the health risks of lead exposure, we would be basing our criteria on the number of children brought into hospital emergency rooms with lead poisoning rather than on the threats it poses to their neurobehavioral development. No parent, and no community, would tolerate such a definition these days.
The author declares he has no competing financial interests.
Bernard Weiss
University of Rochester
Rochester, New York
E-mail: bernard_weiss@urmc.rochester.edu
References
Bellinger DC. 2006. Neurobehavioral assessment in studies of exposures to neurotoxicants. In: Neurotoxicity and Developmental Disorders (Davidson PW, Myers CJ, Weiss B, eds). San Diego, CA:Elsevier Academic Press, 263-300.
CDC. 1991. Preventing Lead Poisoning in Young Children. Atlanta, GA:Centers for Disease Control and Prevention.
McEwen GN Jr, Renner G. 2006. Validity of anogenital distance as a marker of in utero phthalate exposure. Environ Health Perspect 114:A19-20.
Rose G. 1981. Strategy of prevention: lessons from cardiovascular disease. BMJ 282:1847-1851.
Sharpe RM. 2001. Hormones and testis development and the possible adverse effects of environmental chemicals. Toxicol Lett 120:221-322. [CrossRef].
Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. 2005. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 113:1056-1061.
Weiss B. 1988. Neurobehavioral toxicity as a basis for risk assessment. Trends Pharmacol Sci 9:59-62. [CrossRef].
Anogenital Distance: Bailey and Renner Respond
In his letter, Weiss misrepresents the arguments presented in our letter (McEwen and Renner 2006) regarding the study of Swan et al. (2005). We pointed out that a value for "normal" anogenital distance (AGD) is not known and that without this information, "abnormal" AGD values cannot be determined. Swan et al. (2005) measured AGD in a limited number of subjects (134 boys) who varied widely in age, height, and weight. This small sample size is inadequate to determine a normal AGD value, and there are no historical control data for AGD in male human infants using a definition of AGD comparable to the one used by Swan et al.
Although the significance of AGD values in humans, if any, is unknown, it is clear that a meaningful study with AGD as the end point of interest requires knowledge of normal values as a prerequisite. Further, the lack of knowledge of normal AGD values is only one of the significant limitations of the study by Swan et al. (2005); others were identified in our previous letter (McEwen and Renner 2006).
The authors are employed by advocacy groups that represent the interests of the cosmetic, toiletry, and fragrance industry.
John E. Bailey
Cosmetic, Toiletry and Fragrance Association
Washington, DC
E-mail: baileyj@ctfa.org
Gerald Renner
Colipa
The European Cosmetic Toiletry and
Perfumery Association
Brussels, Belgium
References
McEwen GN Jr, Renner G. 2006 Validity of anogenital distance as a marker of in utero phthalate exposure. Environ Health Perspect 114:A19–20.
Swan SH, Main KM, Liu F, Stewart SL, Kruse RI, Calafat AM, et al. 2005 Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 113:1056–1061.