Application of Toxicologically Informed Relative Potency Factors to Examine Associations between Water Disinfection Byproducts and Birth Defects

We used toxicologically informed relative potency factors (RPFs) to compare RPF-weighted versus unweighted epidemiologic analyses of five birth defects (atrial septal defect [ASD], ventricular septal defect [VSD], tetralogy of Fallot [TOF], cleft palate without cleft lip, and obstructive genitourinary defects [OGD]) and various disinfection byproduct (DBP) mixtures in drinking water. We derived RPFs for four trihalomethanes (THMs) and nine haloacetic acids (HAAs) from published animal developmental bioassays using benchmark dose models at 10% responses, estimated adjusted odds ratios (aORs) for RPF-weighted quintile 5 (vs 1) DBP mixture sums, and compared the RPF-weighted and unweighted aORs. RPFs were generally higher for brominated DBP species (e.g., HAA RPF10s from mouse whole embryo culture dysmorphogenesis data: monobromoacetic acid [MBAA] = 1.00, trichloroacetic acid [TCAA] = 0.0011, and dichloroacetic acid [DCAA] = 0.0005), which occurred at lower concentrations than chlorinated species. For THM mixtures, aORs changed <10% with RPF weighting, except for TOF (+19%) for the sum of brominated THMs (tribromomethane + bromodichloromethane + dibromochloromethane). We detected >10% aOR changes for HAA3 (TCAA + DCAA + dibromoacetic acid) with TOF and OGD; HAA5 (HAA3 + monochloroacetic acid + MBAA) with ASD, TOF, and OGD; HAA6 (all brominated HAAs) with TOF; and HAA9 (HAA5 + tribromoacetic acid + bromochloroacetic acid + bromodichloroacetic acid + dibromochloroacetic acid) with OGD. The results suggest that unweighted DBP metrics may reasonably estimate risks of regulated DBPs, but this should be examined elsewhere based on individual-level estimates, which should be prone to less exposure measurement error.