Plasma dioxin levels and cause-specific mortality in an occupational cohort of workers exposed to chlorophenoxy herbicides, chlorophenols and contaminants.

BACKGROUND: We recently reported increased risks for all cancers and urinary cancers in workers exposed to chlorophenoxy herbicides using data from the Dutch herbicide cohort study. These risks could not be linked to the qualitative exposure proxies available. Here, we re-investigate exposure-response relationships using a (semi)quantitative measure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. METHODS: Plasma TCDD levels of 187 workers were used to develop a predictive model for TCDD exposure. Cox proportional hazards model was used to investigate associations between time-varying TCDD exposure and cause-specific mortality. Sensitivity analyses were performed to assess the impact of key assumptions in exposure assessment. RESULTS: Predicted TCDD levels were associated with mortality from all causes (HR 1.08; 95% CI 1.03 to 1.13), ischaemic heart disease (IHD; HR 1.19; 95% CI 1.08 to 1.32) and non-Hodgkin's lymphoma (NHL; HR 1.36; 95% CI 1.06 to 1.74). No relationships were found between TCDD exposure and mortality from all cancers, respiratory or urinary cancers, which were previously linked to qualitative proxies of TCDD exposure in this cohort. Sensitivity analyses showed that results were relatively robust to slight changes in exposure estimation. CONCLUSIONS: Modelled TCDD exposure does not explain the previously reported increased risks for cancer mortality in this cohort except for a possible association with NHL. A small increase in ischaemic heart disease was observed, however we cannot exclude that this finding was due to residual confounding. Although risk estimates for some of the rarer outcomes were still rather imprecise, we do not expect more precise estimates from longer follow-up of this cohort due to the long time-span since last exposure to TCDD.

Changes in lymphocyte subsets in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

OBJECTIVES: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to have toxic effects on the haematopoietic system in animals but epidemiological studies in humans have shown inconsistent results. In this cross-sectional study we investigated changes in peripheral blood cell counts and lymphocyte subsets among workers from a Dutch historical cohort occupationally exposed to chlorophenoxy herbicides and contaminants including TCDD. METHODS: Forty-seven workers who had been exposed to high levels of TCDD in the past and 38 low-exposed workers were included in the current investigation. Complete blood counts and differential and major lymphocyte subsets were analysed. Current plasma levels of TCDD (TCDD(current)) were determined by high-resolution gas chromatography/isotope-dilution high resolution mass spectrometry. TCDD blood levels at the time of last exposure (TCDD(max)) were estimated using a one-compartment first order kinetic model. RESULTS: Cell counts and lymphocyte subsets were similar between high- and low-exposed workers, except for a non-dose dependent increase in CD4/CD8 ratio among high-exposed workers. Interestingly, most lymphocyte subsets, in particular the B cell compartment, showed a decrease with increasing levels of both TCDD(current) and TCDD(max). CONCLUSIONS: Overall, our study showed that plasma TCDD levels had no effect on white blood cell counts and major subsets. However, a non-significant decrease in most lymphocyte subsets was noted, with the strongest effect for B cells. The latter finding may suggest that dioxin exposure might have an adverse impact on the haematopoietic system and lends some support to B cell lymphoma induction by dioxin.

Long-term effects on humoral immunity among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

OBJECTIVES: Epidemiological studies have shown inconsistent effects on immunological parameters in subjects exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study we investigated changes in humoral immunity and prevalence of atopic diseases among workers from a Dutch historical cohort occupationally exposed to chlorophenoxy herbicides and contaminants including TCDD. METHODS: 45 workers who had been exposed to high levels of TCDD in the past and 108 non-exposed workers (39 from the same factory as the exposed subjects (internal control group) and 69 from a comparable factory but without TCDD exposure (external control group)) were included in the study. Blood immunoglobulin (Ig) and complement factor (C) concentrations and specific IgE antibodies to a panel of common allergens were measured using quantitative nephelometry or ELISA. TCDD plasma levels were measured and back-extrapolated to the time of last exposure (TCDDmax) using a one-compartment first order kinetic model. RESULTS: A borderline significant negative association between both current and predicted TCDD levels and C4 was found in multivariate analyses (ß = -0.020; 95% CI = -0.040-0.010 and ß = -0.020; 95% CI = -0.030-0.00, respectively). History of eczema was significantly associated with current TCDD levels in both crude (OR = 1.5; 95% CI = 1.03-2.2) and adjusted models (OR = 1.7; 95% CI = 1.08-2.7). CONCLUSIONS: Our results do not support an association between TCDD exposure and markers of humoral immunity except possibly C4. Interestingly, decreased levels of C4 have been linked to lymphoma risk, which provides some support to the putative link between TCDD and non-Hodgkin lymphoma.

Plasma Cytokine Concentrations in Workers Exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

OBJECTIVES: Few epidemiological studies have studied the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on blood cytokine levels. In this study we investigated changes in plasma levels of a large panel of cytokines, chemokines, and growth factors among workers from a Dutch historical cohort occupationally exposed to chlorophenoxy herbicides and contaminants including TCDD. METHODS: Eighty-five workers who had been exposed to either high (n = 47) or low (n = 38) TCDD levels more than 30 years before serum collection were included in the current investigation. Plasma level of 16 cytokines, 10 chemokines, and 6 growth factors were measured. Current plasma levels of TCDD (TCDD(current)) were determined by high-resolution gas chromatography/isotope-dilution high-resolution mass spectrometry. TCDD blood levels at the time of last exposure (TCDD(max)) were estimated using a one-compartment first order kinetic model. RESULTS: Blood levels of most analytes had a negative association with current and estimated past maximum TCDD levels. These decreases reached formal statistical significance for fractalkine, transforming growth factor alpha (TGF-α), and fibroblast growth factor 2 (FGF2) with increasing TCDD levels. CONCLUSION: Our study showed a general reduction in most analyte levels with the strongest effects for fractalkine, FGF2, and TGF-α. These findings suggest that TCDD exposure could suppress the immune system and that chemokine and growth factor-dependent cellular pathway changes by TCDD may play role in TCDD toxicity and associated health effects.

Changes in serum markers indicative of health effects in vineyard workers following exposure to the fungicide mancozeb: an Italian study.

The aim of this study was to investigate the health effects induced by exposure to the fungicide mancozeb in Italian vineyard workers. Ninety-three Italian subjects entered the study - 48 vine-growers intermittently exposed to mancozeb and 45 healthy controls. The subjects were investigated three times: before the seasonal application of pesticides (T0), 30 days after the beginning of the application period (T30), and 45 days after T0 (T45). At T0 the comparison between agricultural workers and controls showed a higher prevalence of cold or flu symptoms, a statistically significant lower percentage of monocytes, higher absolute count of T lymphocytes, CD4 and natural killer cells, and lower plasma levels of IgA and IgM in workers. Such differences were not confirmed at T30 and T45. In fact at T30 in exposed workers, besides a significant increase of urinary ethylenethiourea, confirming mancozeb exposure, T lymphocytes, CD4 and natural killer cells, IgA and IgM returned to values comparable to those observed in controls. Moreover, no other differences in clinical signs, haematological, and immune parameters, such as the immune functional capability evaluated as a response to hepatitis B vaccination, was observed. Altogether the differences between exposed and controls were not consistently correlated to any clinical impairment and suggest that the seasonal application of mancozeb does not pose a significant health risk to exposed subjects.