Glycol Ethers and Congenital Malformations

To the Editor:

The recent work by Cordier et al¹ suggests several specific associations between solvent exposure during early pregnancy and the risk of congenital malformations. Contrary to the opinion of the investigators, we consider that the findings do not support the conclusions as presented.

The key concern with this work is the very weak case for the biological plausibility of the findings. The authors state that several solvents are developmental toxicants for animals, and cite Bruckner et al² in support. This association between solvent exposure and developmental effects thus underpins the authors’ hypothesis that exposure to oxygenated solvents, specifically glycol ethers, could be associated with developmental effects in humans. Although it is true that certain glycol ethers are associated with developmental toxicity in animals, this does not apply to all glycol ethers, as illustrated by Bruckner et al² and other reviews of the toxicity of glycol ethers.³ In fact, the only glycol ethers considered to be developmentally toxic in animal studies with potential relevance to humans are ethylene glycol methyl ether, ethylene glycol ethyl ether, diethylene glycol methyl ether, and the β-isomer of propylene glycol methyl ether, 2-methoxypropan-1-ol.³

A specific example of the lack of biological plausibility is the conclusion that associations identified between malformations and the urinary levels of a metabolite of diethylene glycol ethyl ether (DEGEE) support the study hypothesis and warrant further investigation. Several developmental toxicity studies on DEGEE³ demonstrate an absence of developmental findings up to doses that were maternally toxic, that is, this substance is not a developmental toxicant. In addition, the confidence intervals for the associations were large (2.4–50 for oral clefts; 1.1–8.2 for limb). Taking these together, it is unlikely that exposure to DEGEE is a contributing factor in malformations; therefore, it seems plausible that these results may be due to random error, bias, or unmeasured confounding.

Birth defects are a tragic birth outcome. Identifying an etiology by which a malformation can be prevented, such as with folic acid and neural tube defects, is an important public health contribution. However, given the relatively weak associations reported by Cordier et al¹ and the minimal biological plausibility, we do not believe that the results corroborate the researchers’ concern that occupational exposure to glycol ethers during pregnancy is a contributing factor in the development of congenital malformations.

ACKNOWLEDGMENTS

I thank Carol Burns, Jeff Kelsey, Erik Rushton, and the Oxygenated Solvents Producers Association and Glycol Ethers Industry Association for their advice.

Nicholas Ball

The Dow Chemical Company, Horgen, Switzerland, [email protected]