{"id":11334,"date":"2022-11-14T09:25:12","date_gmt":"2022-11-14T14:25:12","guid":{"rendered":"https:\/\/blogs.edf.org\/health\/?p=11334"},"modified":"2022-11-16T09:30:04","modified_gmt":"2022-11-16T14:30:04","slug":"anti-androgenic-chemicals-as-a-class-of-related-substances-with-cumulative-toxicological-effects","status":"publish","type":"post","link":"https:\/\/blogs.edf.org\/health\/2022\/11\/14\/anti-androgenic-chemicals-as-a-class-of-related-substances-with-cumulative-toxicological-effects\/","title":{"rendered":"Anti-androgenic chemicals as a class of related substances with cumulative toxicological effects"},"content":{"rendered":"

Maricel Maffini, consultant,<\/em> and Tom Neltner<\/em><\/a>, Chemicals Policy Director<\/em><\/p>\n

Scientists and regulators have known for decades that certain chemicals disrupt the actions of male hormones\u2014identified collectively as androgens<\/em>\u2014in the body. Because of their effects, these chemicals are called anti-androgens or anti-androgenic chemicals.<\/p>\n

During gestation, fetal testes begin producing testosterone, the critical hormone required to develop reproductive organs and genitalia. Insufficient production of testosterone leads to malformation of the genital tract that may need corrective surgery in infant boys and may result in reproductive health problems later in life. Ortho-phthalates<\/a> (aka phthalates), known to interfere with the production of fetal testosterone, are considered anti-androgenic chemicals.<\/p>\n

Although phthalates are perhaps the most recognizable group of anti-androgenic chemicals in the diet, there are others<\/a>, including bisphenol A (BPA), propyl paraben, and certain pesticides<\/a> used in food crops. Because they cause similar harmful effects, namely adverse health outcomes for male reproductive system, their safety assessment must take into account the cumulative effects<\/a> of similar substances in the diet as established by law<\/a>. But what does \u201ccumulative effect\u201d mean? Below, we use a recent study to explain what it means, why it is important, and why FDA is failing.<\/p>\n

Biology is not math and the concept of something from nothing<\/strong><\/p>\n

In 2021, Justin Conley and colleagues at the U.S. Environmental Protection Agency published a \u00a0fascinating study<\/a> in which pregnant rats were exposed to mixtures of 15 anti-androgenic chemicals during the time of fetal sexual differentiation of the reproductive tract and analyzed the effects of the mixtures in the male pups. The mixture contained the following chemicals:<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Table 1: List of anti-androgenic chemicals use in the Conley et al. cumulative effect study<\/td>\n<\/tr>\n
Chemical<\/td>\nLikely in the diet<\/td>\nUses<\/td>\nRegulatory status<\/td>\n<\/tr>\n
Benzylbutyl phthalate<\/td>\nYes<\/td>\nFood additive<\/td>\nUse abandoned<\/td>\n<\/tr>\n
Dibutyl phthalate<\/td>\nYes<\/td>\nFood additive<\/td>\nUse abandoned<\/td>\n<\/tr>\n
Dicyclohexyl phthalate<\/td>\nYes<\/td>\nFood additive<\/td>\nIn use<\/td>\n<\/tr>\n
Diethylhexyl phthalate<\/td>\nYes<\/td>\nFood additive<\/td>\nIn use<\/td>\n<\/tr>\n
Dihexyl phthalate<\/td>\nYes<\/td>\nFood additive<\/td>\nUse abandoned<\/td>\n<\/tr>\n
Diisobutyl phthalate<\/td>\nYes<\/td>\nFood additive<\/td>\nUse abandoned<\/td>\n<\/tr>\n
Diheptyl phthalate<\/td>\nUnknown<\/td>\n <\/p>\n

Not authorized for use in food<\/td>\n<\/tr>\n

Diisoheptyl phthalate<\/td>\nUnknown<\/td>\n<\/tr>\n
Dipentyl phthalate<\/td>\nUnknown<\/td>\n<\/tr>\n
Linuron<\/td>\nYes*<\/td>\nPesticide<\/td>\nIn use<\/td>\n<\/tr>\n
Prochloraz<\/td>\nYes*<\/td>\nPesticide<\/td>\nIn use<\/td>\n<\/tr>\n
Procymidone<\/td>\nYes*<\/td>\nFungicide<\/td>\nIn use<\/td>\n<\/tr>\n
Pyrifluquinazon**<\/td>\nYes*<\/td>\nPesticide<\/td>\nIn use<\/td>\n<\/tr>\n
Vinclozolin<\/td>\nYes*<\/td>\nFungicide<\/td>\nIn use<\/td>\n<\/tr>\n
p,p\u2019-DDE***<\/td>\nYes*<\/td>\nPesticide<\/td>\nMetabolite of DDT (banned). Persist in the environment.<\/td>\n<\/tr>\n
* U.S. Department of Agriculture Pesticide Data Program (PDP) database https:\/\/apps.ams.usda.gov\/pdp<\/a><\/p>\n

** Pyrufluquinazon is a PFAS pesticide (heptafluoroisopropyl)<\/p>\n

*** 1,1\u2032 -(2,2-Dichloroethene-1,1-diyl)bis(4-chlorobenzene)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

For each individual chemical, the researchers knew the levels at which the substance alone produced no observable adverse effects (NOAEL) in the pups. They prepared mixtures where each chemical was added at its own NOAEL and made dilutions of the mixture up to 1,000 times lower than the NOAELs. See Figure 1.<\/p>\n

\"\"<\/a><\/p>\n

Figure 1:<\/strong> Schematic representation of the experimental design and summary of results<\/em><\/p>\n

Since the amount of each of the 15 chemicals in the mixture was below the NOAEL, there would have been no observed effect if the chemicals did not have a cumulative effect. Instead, all six adverse effects were seen even when the concentrations of the chemicals were diluted by half. In one case, an adverse effect was seen when the mixture was diluted 15-fold. In short, they got something (an adverse effect) from nothing (levels that, individually, did not cause any adverse effects).<\/p>\n

Researchers concluded that the mixture of 15 anti-androgenic chemicals \u201cacted cumulatively to produce adverse effects at doses below which any individual chemical had been shown to produce an effect alone.<\/strong>\u201d [Emphasis added.]<\/p>\n

In other words, serious harm occurred from the combination of chemicals in amounts considered \u201csafe,\u201d strengthening the concept of \u201csomething from nothing\u201d.<\/p>\n

Why should we care about cumulative effects of chemicals in the diet?<\/strong><\/p>\n

First, we are underestimating the health risks. The current approach is to do safety assessments on one chemical at a time, in isolation from others. Based on that individual chemical\u2019s toxicity, FDA establishes a \u201csafe\u201d exposure amount above which the risk of harm increases.<\/p>\n

In reality, however, we are exposed to multiple chemicals every time we eat, and each one can interact with the same organs and functions. As shown by Conley and others (here<\/a>, here<\/a>, here<\/a>),<\/p>\n

Second, the law mandates<\/a> that, when assessing the safety of a chemical\u2019s use as an additive or food contact substance, FDA consider related substances already in the diet that are structurally similar (those usually have similar toxicity) and those that are known to cause similar effects even though they are structurally different.<\/p>\n

The FDA has been asleep at the wheel<\/strong><\/p>\n

According to FDA\u2019s regulation<\/a>s, chemicals that \u201ccause similar or related pharmacological effects\u201d must be considered as a class, and \u201cin the absence of evidence to the contrary, as having additive toxic effects.\u201d<\/p>\n

Unfortunately, both FDA and industry continue to ignore common sense requirement despite the law and have not acted on a two-year old petition<\/a> highlighting the failure. See also HERE<\/a> and HERE<\/a>.<\/p>\n

Conley and his colleagues concluded that \u201cthere is growing support for the idea that cumulative assessment groups need to include all chemicals that produce common adverse effects<\/strong> in an assessment of chemical risk\u201d regardless of the molecular pathways each utilize to cause the adverse effect. A new study<\/a> published in late July adds support this conclusion. [Emphasis added]<\/p>\n

Conclusions<\/strong><\/p>\n

The harm caused by anti-androgenic chemicals occurs before children are born and the consequences last a lifetime. Predicting toxicity by chemical structure alone is inadequate and shortsighted likely leading to underestimation of harm. Assessing classes of chemicals based on common adverse effect should be the default safety assessment approach.<\/p>\n

Congress was right to include consideration of cumulative effects the law in 1958. FDA failed to follow its own regulation. Such neglect leaves American families at higher risk for chronic diseases.<\/p>\n

 <\/p>\n

 <\/p>\n

 <\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

Maricel Maffini, consultant, and Tom Neltner, Chemicals Policy Director Scientists and regulators have known for decades that certain chemicals disrupt the actions of male hormones\u2014identified collectively as androgens\u2014in the body. Because of their effects, these chemicals are called anti-androgens or anti-androgenic chemicals. During gestation, fetal testes begin producing testosterone, the critical hormone required to develop …<\/p>\n","protected":false},"author":69548,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[114066,69,114055],"tags":[92366,114004,39162,91633,107239],"coauthors":[114044],"class_list":["post-11334","post","type-post","status-publish","format-standard","hentry","category-adverse-health-effects","category-fda","category-phthalates","tag-chemicals-in-food","tag-cumulative-effect","tag-cumulative-exposure","tag-fda","tag-food-chemicals"],"acf":[],"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/posts\/11334","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/users\/69548"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/comments?post=11334"}],"version-history":[{"count":0,"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/posts\/11334\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/media?parent=11334"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/categories?post=11334"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/tags?post=11334"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/blogs.edf.org\/health\/wp-json\/wp\/v2\/coauthors?post=11334"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}