Urine 1,6-Hexamethylene Diamine (HDA) Levels Among Workers Exposed to 1,6-Hexamethylene Diisocyanate (HDI)

Abstract

Urinary 1,6-hexamethylene diamine (HDA) may serve as a biomarker for systemic exposure to 1,6-hexamethylene diisocyanate (HDI) in occupationally exposed populations. However, the quantitative relationships between dermal and inhalation exposure to HDI and urine HDA levels have not been established. We measured acid-hydrolyzed urine HDA levels along with dermal and breathing-zone levels of HDI in 48 automotive spray painters. These measurements were conducted over the course of an entire workday for up to three separate workdays that were spaced approximately 1 month apart. One urine sample was collected before the start of work with HDI-containing paints and subsequent samples were collected during the workday. HDA levels varied throughout the day and ranged from nondetectable to 65.9 microg l(-1) with a geometric mean and geometric standard deviation of 0.10 microg l(-1) +/- 6.68. Dermal exposure and inhalation exposure levels, adjusted for the type of respirator worn, were both significant predictors of urine HDA levels in the linear mixed models. Creatinine was a significant covariate when used as an independent variable along with dermal and respirator-adjusted inhalation exposure. Consequently, exposure assessment models must account for the water content of a urine sample. These findings indicate that HDA exhibits a biphasic elimination pattern, with a half-life of 2.9 h for the fast elimination phase. Our results also indicate that urine HDA level is significantly associated with systemic HDI exposure through both the skin and the lungs. We conclude that urinary HDA may be used as a biomarker of exposure to HDI, but biological monitoring should be tailored to reliably capture the intermittent exposure pattern typical in this industry.

Hemoglobin adducts in workers exposed to 1,6-hexamethylene diisocyanate

“…HDA in acid-hydrolyzed urine and plasma are the only validated biomarkers to date for short-term (Tinnerberg et al 1995, Maître et al 1996, Gaines et al 2010) and cumulative exposure to HDI monomer (Flack et al 2010a). Once in the body, the isocyanato moiety (NCO) may be hydrolyzed to an amine (e.g., HDA), catalyzed by bicarbonate in the blood (Berode et al 1991), or may react with proteins, such as albumin and hemoglobin (Hb), to form protein adducts.…”

“…Moreover, a biphasic elimination pattern has been described for diisocyanate-derived amines, thought to result from the rapid urinary excretion of short-term metabolites within a few hours (Brorson et al 1990b, Tinnerberg et al 1995), followed by the excretion of long-lived protein adducts days later (Lind et al 1997). The presence of HDA in the majority of first-day, pre-exposure urine samples among HDI-exposed spray painters, also indicated the slow elimination of protein conjugates accumulated during the work week (Gaines et al 2010). In addition to being an indicator of past exposure to diisocyanates, protein adducts may contribute to the pathogenesis of diisocyanate-induced asthma by their action as protein carriers in presenting HDI to the immune system (Wisnewski et al 2000).…”

Factors affecting variability in the urinary biomarker 1,6-hexamethylene diamine in workers exposed to 1,6-hexamethylene diisocyanate

“…The use of urinary 1,6-hexamethylene diamine (HDA) as a biomarker for inhalation exposure to 1,6-hexamthylene diisocyanate (HDI) has been established. 3–7 Previously, we demonstrated a quantitative linear relationship between dermal exposure to HDI and urine HDA levels. 3 We further concluded that creatinine should be used as an independent variable in exposure modeling to account for the water content in the urine sample collected from a worker exposed to HDI.…”

“…3–7 Previously, we demonstrated a quantitative linear relationship between dermal exposure to HDI and urine HDA levels. 3 We further concluded that creatinine should be used as an independent variable in exposure modeling to account for the water content in the urine sample collected from a worker exposed to HDI. 3,8 However, in our exposure models relating inhalation and dermal HDI exposure to urine HDA levels, considerable intra- and inter-person variability was observed, 3 which would compromise the use of urine HDA as a biomarker for occupational exposure to HDI.…”

“…3 We further concluded that creatinine should be used as an independent variable in exposure modeling to account for the water content in the urine sample collected from a worker exposed to HDI. 3,8 However, in our exposure models relating inhalation and dermal HDI exposure to urine HDA levels, considerable intra- and inter-person variability was observed, 3 which would compromise the use of urine HDA as a biomarker for occupational exposure to HDI. To effectively use individual urine HDA levels in monitoring exposure, evaluating personal protection, and establishing regulatory compliance, determining the cause(s) of the variability is critical.…”