ACC's High Phthalates Panel Disputes Conclusions of Recent DINP Study

WASHINGTON (November 26, 2018) – The Chemical Watch article published Nov. 8, 2018, entitled “‘Moderate Evidence’ linking DINP to male reproductive effects,” announced the results of a recent study (Radke et al. 2018), claiming there is “moderate evidence” DINP may cause male reproductive effects at levels seen in human populations. The American Chemistry Council’s (ACC) High Phthalates Panel (HPP) has identified several concerns with this publication that it intends to highlight. This comment focuses specifically on DINP, as it is one of the high molecular weight phthalates of concern to the panel.

Radke et al (2018) publication

This study, entitled: “Phthalate exposure and male reproductive outcomes: A systematic review of the human epidemiologic evidence,” is a review of existing epidemiological studies of specific phthalates, some of which are classified in Europe for adverse reproductive effects (DEHP, DBP, DIBP and BBP) and some of which are not classified for such effects following rigorous regulatory reviews (DEP and DINP).

• The study does not provide any new evidence. Rather, it is a review of existing studies that were included in the European Chemicals Agency (ECHA) Risk Assessment Committee (RAC)’s exhaustive review of the reproductive toxicity data on DINP.
• In its opinion published on March 9, 2018¹, the ECHA RAC opinion concluded “there is no evidence for effects of DINP on fertility in humans.” It is telling that this 35-page opinion was not cited by Radke et al. (2018).
• Furthermore, the ECHA RAC performed an in-depth review of key studies relevant to DINP (both those required by regulation and published academic and industry studies) and concluded based on both the epidemiology and animal data that: “Overall, RAC concluded that no classification for DINP for either effects on sexual function and fertility, or for developmental toxicity is warranted.”
• Most importantly, in reaching its flawed conclusion of “moderate evidence” of an association between DINP exposure and male reproductive outcomes, Radke et al. 2018 made several significant errors that render their conclusions less than valid:
  •  
  • As an example, Radke et al. 2018 claim there is a moderate relationship between DINP exposure and sperm parameters based on “consistency across studies for morphology,” specifically citing a finding² of statistically significant inverse relationship between DINP exposure and sperm morphology. However, a review of the paper indicates that Radke et al. 2018 confused the findings on motility for morphology.
• Many of the available studies were incorrectly interpreted and in some cases, a mere trend is misstated as an association in instances where the authors of the studies cited have clearly indicated that such does not exist.
  •  
  • For example, Pan et al. 2015³ is cited as evidence of an inverse relationship between DINP exposure and normal sperm morphology and sperm motility. First, the findings in Pan et al. 2015 were not statistically significant. Secondly, Pan et al. 2016⁴ conclusively indicates that the implied inverse relationship does not exist. For example, with respect to sperm motility, Pan et al. 2016 states “sperm motility was not associated with any phthalate metabolites or groups.” With respect to sperm morphology, inverse relationships were found for some phthalate metabolites, with the exception of MiNP and MCiOP, the two metabolites of DINP analyzed.
  •  
  • In another example, citing Specht et al. 2014,⁵ Radke et al. 2018 imply that there is an association between proxy-MiNP and sperm concentration. However, Specht et al. 2014 clearly state that “proxy-MiNP was not associated with any of the semen parameters,” including semen volume, concentration and total count.
  •  
  • Radke et al. 2018 cite Meeker and Ferguson 2014⁶ as one of three papers that found “decreasing testosterone levels with increasing DINP exposure,” specifically in adolescent boys (ages 12-20). However, the discussion section of Meeker and Ferguson 2014 clearly states thus: “The lack of association between phthalates and T among adolescent boys (ages 12–20) in the present study may be due to the widely varying levels of T in this age group and our inability to account for pubertal development in our analysis.”
  •  
  • The authors used inaccurate methodologies leading to unsupportable conclusions, many of which are detailed in a previous ACC letter to the US EPA (April 20, 2018).
• The data points highlighted as evidence of an adverse effect are small (single-digit percent changes that are likely results of random variation), often isolated and inconsistent even across studies by the same authors. In all cases, Radke et al. 2018 fail to explain the clinical significance of any of the results.

Chemical Watch article

The Chemical Watch article overstates that the published study (Radke et al., 2018) was “led by the U.S. Environmental Protect Agency” when in fact the authors of the study specifically state “the views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.”

Overall, in view of the many flaws in this paper, the ACC HPP and CEFIC European Plasticisers are in the process of drafting a detailed letter to the editor of Environmental International, where the Radke et al. 2018 paper was published, requesting that these flaws be adequately addressed and the erroneous conclusions corrected accordingly.

¹ECHA RAC opinion proposing harmonized classification and labeling at EU level of DINP – https://echa.europa.eu/documents/10162/56980740-fcb6-6755-d7bb-bfe797c36ee7.

²Jurewicz, J., M. Radwan, W. Sobala, D. Ligocka, P. Radwan, M. Bochenek et al.: Human urinary phthalate metabolites level and main semen parameters, sperm chromatin structure, sperm aneuploidy and reproductive hormones. Reproductive Toxicology 42: 232-241 (2013).

³Pan, Y., J. Jing, F. Dong, Q. Yao, W. Zhang, H. Zhang et al.: Association between phthalate metabolites and biomarkers of reproductive function in 1066 Chinese men of reproductive age. Journal of Hazardous Materials 300: 729-736 (2015).

⁴Pan, Y., J. Jing, L.W.Y. Yeung, N. Sheng, H. Zhang, B. Yao et al.: Associations of urinary 5-methyl-2′-deoxycytidine and 5-hydroxymethyl-2′-deoxycytidine with phthalate exposure and semen quality in 562 Chinese adult men. Environ Int 94: 583-590 (2016).

⁵ Specht, I.O., G. Toft, K.S. Hougaard, C.H. Lindh, V. Lenters, B.A.G. Jönsson et al.: Associations between serum phthalates and biomarkers of reproductive function in 589 adult men. Environ Int 66: 146-156 (2014).

⁶ Meeker, J.D., and K.K. Ferguson: Urinary phthalate metabolites are associated with decreased serum testosterone in men, women, and children from NHANES 2011-2012. The Journal of clinical endocrinology and metabolism 99(11): 4346-4352 (2014).