Expanded assessment of xenobiotic associations with antinuclear antibodies in the United States, 1988–2012

Background: The prevalence of autoimmunity in the U.S. has increased recently for undetermined reasons. Little is known about associations between autoimmunity and environmental causes. Objectives: In a large representative sample of the U.S. population, we expanded our prior exploratory study of how exposures to selected xenobiotics and dioxin-like (DL) mixtures relate to antinuclear antibodies (ANA), the most common biomarker of autoimmunity. Methods: We analyzed cross-sectional data on 12,058 participants aged ≥ 12 years from three time periods of the National Health and Nutrition Examination Survey between 1988 and 2012, of whom 14% were ANA-positive. We used lognormal regression models and censored-data methods to estimate ANA associations with xenobiotic concentrations overall and in sex, age, and race/ethnicity subgroups. Our analyses adjusted for potential confounders and appropriately handled concentrations below detection limits. Results: Observed ANA associations were positive for most DL compounds and nonDL polychlorinated biphenyls (PCBs), negative for most phthalates, and mixed for other xenobiotic classes. After correcting for multiple comparisons, some associations remained statistically significant. In subgroup analyses, the most significant finding was a positive ANA association with N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine (MHB2) in males, followed by positive associations with 2,2′,3,5′-tetrachlorobiphenyl (PCB 44), 2,2′,4,5′-tetrachlorobiphenyl (PCB 49), and 2,2′,3,4′,5′,6-hexachlorobiphenyl (PCB 149) in 12–19 year-olds, and with 3,4,4′,5-tetrachlorobiphenyl (PCB 81), 2,2′,3,3′,4,4′,5,5′,6-nonachlorobiphenyl (PCB 206), and N-acetyl-S-(phenyl)-L-cysteine (PMA) in Mexican Americans. Negative associations were found with mono-benzyl phthalate (MBzP) in 20–49 year-olds and mono-n-butyl phthalate (MnBP) in 12–19 year-olds. In overall analyses, combining stratum-specific results across race/ethnicity strata revealed a positive ANA association with PCB 81 and a negative ANA association with N-acetyl-S-(2-hydroxyethyl)-L-cysteine (HEMA). Discussion: This study identified potential associations between ANA and various xenobiotics. Further investigation to confirm these observations and elucidate effects of certain xenobiotics on immune regulation could have important mechanistic, preventive, and treatment implications for a variety of immune-mediated disorders.