Current serum levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin in phenoxy acid herbicide applicators and characterization of historical levels.

BACKGROUND: Workers who sprayed phenoxy acid herbicides, especially those who sprayed before 1975, may have been exposed to significant amounts of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent animal carcinogen present in herbicide preparations as a contaminant. PURPOSE: The aims of this study were (a) to determine serum levels of TCDD in a representative sample of workers occupationally exposed to the agent during the spraying of phenoxy acid herbicides; (b) to compare serum levels in workers exposed before 1965, when concentrations in herbicide products were unregulated and high, with levels in workers exposed after 1974, when concentrations were lower as a result of government regulations worldwide; and (c) to examine the correlation, if any, between serum levels and duration of employment in spraying. METHODS: Thirty-seven subjects were randomly selected from a group of 654 men who had sprayed the herbicides 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D) in Australia for at least 12 months. The workers were classified as follows: eight who sprayed only before 1965, nine who sprayed only during the period after 1964 and before 1975, and 20 who sprayed during the period after 1974 and before 1991. Serum from the workers was analyzed for TCDD by high-resolution gas chromatography and high-resolution mass spectrometry at a detection limit of 0.6 parts per trillion (ppt) on a lipid-weight basis. In addition, rates of exposure to TCDD were estimated, as were TCDD serum concentrations at termination of employment and intensity of herbicide use. RESULTS: Only one worker, with a serum TCDD level of 34 ppt, had a serum level higher than the maximum level of 26 ppt reported for the general population. Assuming a half-life of 7.1 years, we estimated the mean exposure rates to be 2.7, 2.3, and 0.06 ppt/mo for the three epochs, respectively. We found the highest serum level of TCDD at the time of cessation of employment to be 329 ppt. Calendar period and intensity of use of 2,4,5-T and 2,4-D were statistically significant determinants of rate of exposure to TCDD, but 2,4-D was associated with exposure rate only for the pre-1975 periods. Estimated rates prior to 1965 were more than an order of magnitude higher than those after 1974. CONCLUSION: The highest estimated exposure rate was 20.7 ppt/mo, which suggests that some sprayers may have been exposed to levels comparable with those that produce cancer in laboratory animals.     

Cancer incidence among pesticide applicators exposed to metolachlor in the Agricultural Health Study

Metolachlor is one of the most widely used herbicides in the United States. We evaluated the incidence of cancer among pesticide applicators exposed to metolachlor in the Agricultural Health Study, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina. A total of 50,193 pesticide applicators were included. Detailed information on pesticide exposure and lifestyle factors was obtained from self-administered enrollment questionnaires completed between 1993 and 1997; average length of follow-up was 7.33 years. Two metolachlor exposure metrics were used : (i) lifetime days personally mixed or applied metolachlor and (ii) intensity-weighted lifetime days (lifetime days x an intensity level). Poisson regression analysis was used to estimate relative risks (RR) and 95% confidence intervals (95%CI) for cancer subtypes by tertiles of metolachlor exposure. No clear risk for any cancer subtype was found for exposure to metolachlor. A significantly decreased RR was found for prostate cancer in the highest category of lifetime days exposure (RR = 0.59; 95%CI, 0.39-0.89) and in the second highest category of intensity-weighted lifetime days exposure (RR = 0.66; 95%CI, 0.45-0.97); however, the test for trend was not significant for either exposure metric. A nonsignificantly increased risk was found for lung cancer with lifetime days exposure in the highest category (RR = 2.37; 95%CI, 0.97-5.82, p-trend = 0.03) but not with intensity-weighted lifetime days. Given the widespread use of metolachlor and the frequent detection of metolachlor in both surface and ground water, future analyses of the AHS will allow further examination of long-term health effects, including lung cancer and the less common cancers.     

Pesticide exposures in children with non-Hodgkin lymphoma

BACKGROUND: The association between pesticide exposure and non-Hodgkin lymphoma (NHL) in adults has been the subject of numerous case-control and cohort studies. However, to the authors' knowledge, data regarding pesticide exposures in children diagnosed with NHL have been lacking. METHODS: The Children's Cancer Group conducted a study comparing 268 children who developed NHL or leukemia with bulk disease with a group of matched, randomly selected regional population controls. The telephone interviews of both the case and control mothers included selected questions regarding occupational and home exposures to pesticides around the time of the index pregnancy and exposure of the child. RESULTS: A significant association was found between risk of NHL and increased frequency of reported pesticide use in the home (odds ratio [OR] = 7.3 for use most days; trend P = 0.05), professional exterminations within the home (OR = 3.0; P = 0.002), and postnatal exposure (OR = 2.4; P = 0.001). Elevated risks were found for T-cell and B-cell lymphomas; for lymphoblastic, large cell, and Burkitt morphologies; and in both young (age < 6 years) and older children. There was an increased risk of NHL with occupational exposure to pesticides (OR = 1.7) that was not significant overall, but that was significant for Burkitt lymphoma (OR = 9.6; P < 0.05). CONCLUSIONS: The results of the current study provide further evidence linking pesticide exposure to the risk of NHL, but the authors were unable to implicate any specific agent.     

Effects of cycloheximide on the induction of CYP1A1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in three human breast cancer cell lines

Treatment of MCF-7, MDA-MB-231 and Hs578-T human breast cancercell lines with 10_–9 M 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) induces CYP1A1 gene expression in the MCF-7 but not inthe MDA-MB-231 or Hs578-T cells. Pretreatment of the cells with10_–5 M cycloheximide results in significantly increasedP4501A1 mRNA levels in all three cells lines. However, in cellsco-treated with 10_–5 M cycloheximide plus 10_–9 MTCDD, an induced response by TCDD was observed in the MCF-7and MDA-MB-231 but not in Hs578-T cells. Gel-retardation assaysof nuclear extracts from the three cell lines complexed witha ³²P-labeled dioxin-responsive element (DRE) gave a TCDD-inducibleretarded band only in the MCF-7 and MDA-MB-231 cells. A retardedband with a similar mobility was observed in nuclear extractsfrom Hs578-T cells treated with either 10_–9 M TCDD orDMSO (solvent control). These results suggest that aryl hydrocarbonnon-responsive MDA-MB-231 and Hs578-T human breast cancer celllines contain the CYP1A1 gene and treatment with cycloheximideincreases both constitutive and TCDD-induced CYP1A1 gene expression.     

Agricultural pesticide use and pancreatic cancer risk in the Agricultural Health Study Cohort

Pancreatic cancer is a rapidly fatal disease that has been linked with pesticide use. Previous studies have reported excess risks of pancreatic cancer with organochlorines such as DDT, however, many other commonly used pesticides have not been examined. To further examine the potential associations between the use of a number of pesticides and pancreatic cancer, we conducted a case‐control analysis in the Agricultural Health Study, one of the largest prospective cohorts with over 89,000 participants including pesticide applicators and their spouses in Iowa and North Carolina. This analysis included 93 incident pancreatic cancer cases (64 applicators, 29 spouses) and 82,503 cancer‐free controls who completed an enrollment questionnaire providing detailed pesticide use, demographic and lifestyle information. Ever use of 24 pesticides and intensity‐weighted lifetime days [(lifetime exposure days) × (exposure intensity score)] of 13 pesticides was assessed. Risk estimates were calculated using unconditional logistic regression controlling for age, smoking, and diabetes. Among pesticide applicators, 2 herbicides (EPTC and pendimethalin) of the 13 pesticides examined for intensity‐weighted lifetime use showed a statistically significant exposure‐response association with pancreatic cancer. Applicators in the top half of lifetime pendimethalin use had a 3.0‐fold (95% CI 1.3–7.2, p‐trend = 0.01) risk compared with never users, and those in the top half of lifetime EPTC use had a 2.56‐fold (95% CI = 1.1–5.4, p‐trend = 0.01) risk compared with never users. Organochlorines were not associated with an excess risk of pancreatic cancer in this study. These findings suggest that herbicides, particularly pendimethalin and EPTC, may be associated with pancreatic cancer. © 2008 Wiley‐Liss, Inc.     

Cancer incidence among pesticide applicators exposed to captan in the Agricultural Health Study

Objective  Captan is a widely used antifungal pesticide whose potential to cause cancer in humans is uncertain. Methods  We evaluated the incidence of cancer among pesticide applicators exposed to captan in the Agricultural Health Study. Detailed information on pesticide exposure and lifestyle factors was obtained from self-administered enrollment questionnaires completed between 1993 and 1997. Results  Of the 48,986 applicators enrolled 4,383 (9%) had applied captan. Median follow-up time was 9.14 years. Poisson regression analysis was used to estimate relative risks (RR) for cancer subtypes by tertiles of captan exposure. We investigated risk for all cancers combined and sites of cancer for which at least 15 cases occurred among captan-exposed applicators. These sites included cancers of the prostate, lung, and colon, blood-related cancers, and colorectal cancers. During follow-up 2,912 incident primary cases of cancer were identified. No association between the highest tertile of captan exposure (>67.375 intensity-weighted days) and development of all cancers (RR = 0.89; 95% CI, 0.71–1.13) or cancer of any specific site was observed. Conclusion  Although our study is limited by low numbers of observed cancer cases and follow-up time of 9.14 years, it does not provide evidence of an increased risk for the development of cancer at the investigated sites. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the National Institute for Occupational Safety and Health, or the Department of Defense.     

Cancer, heart disease, and diabetes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

BACKGROUND: In 1997, the International Agency for Research on Cancer classified 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a group 1 human carcinogen, based largely on four highly exposed industrial cohorts that showed an excess of all cancers combined. In this study, we extended the follow-up period for the largest of these cohorts by 6 years and developed a job-exposure matrix. METHODS: We did cohort mortality analyses involving 5132 chemical workers at 12 U.S. plants by use of life table techniques (U.S. population referent) and Cox regression (internal referent). We conducted exposure-response analyses for 69% of the cohort with adequate work history data and adequate plant data on TCDD contamination. All P values are two-sided. RESULTS: The standardized mortality ratio (SMR) for all cancers combined was 1.13 (95% confidence interval = 1.02-1.25). We found statistically significant positive linear trends in SMRs with increasing exposure for all cancers combined and for lung cancer. The SMR for all cancers combined for the highest exposure group was 1.60 (95% confidence interval = 1.15-1.82). SMRs for heart disease showed a weak increasing trend with higher exposure (P = .14). Diabetes (any mention on the death certificate) showed a negative exposure-response trend. Internal analyses with Cox regression found statistically significant trends for cancer (15-year lag time) and heart disease (no lag). CONCLUSIONS: Our analyses suggest that high TCDD exposure results in an excess of all cancers combined, without any marked specificity. However, excess cancer was limited to the highest exposed workers, with exposures that were likely to have been 100-1000 times higher than those experienced by the general population and similar to the TCDD levels used in animal studies.     

Dichlorvos exposure and human cancer risk: results from the Agricultural Health Study

Objectives We evaluated cancer risk from DDVP (2,2-Dichloroethenyl dimethylphosphate) exposure among pesticide applicators enrolled in the Agricultural Health Study (AHS) cohort. Methods The AHS is a cohort of 57,311 pesticide applicators in North Carolina and Iowa, enrolled from 1993 to 1997 and followed for cancer through 2004. A comprehensive questionnaire collected information on exposure to DDVP and potential confounders. Among the 49,762 licensed pesticide applicators eligible for analysis, 4,613 reported use of DDVP. DDVP exposure was classified as intensity-weighted cumulative exposure days (IWED), calculated as [years of use × days per year × intensity level]. Poisson regression analysis was used to calculate rate ratios (RR) and 95% confidence intervals (CI) to evaluate the association of DDVP exposure among 2,943 incident cases of cancer. Results DDVP exposure was not associated with any cancer studied here. We observed no elevation in risk among lymphohematopoietic cancers, RR = 1.00 (95% CI 0.51, 1.96) and a small excess risk associated with exposure among those with a family history of prostate cancer (RR = 1.18 (95% CI 0.73, 1.82). Conclusion We find little evidence of an association between cumulative lifetime use of DDVP and risk of any cancer at this stage of follow up of the AHS.     

Cancer incidence in England and Wales and New Zealand and in migrants between the two countries.

Risks of cancer incidence in people born in England and Wales and New Zealand (non-Maoris) living in their home countries, and after migration between the two countries, were analysed using data from their national cancer registries. Since these populations are of similar genetic origin, any real differences in cancer incidence between them are likely to reflect the action of environmental or behavioural risk factors. The greatest differences in risk between the countries were for cutaneous melanoma and lip cancer. In each sex, relative risks of these malignancies were 4 or greater for the New Zealand-born in New Zealand compared with English and Welsh natives in their home country, and risks for migrants in each direction were generally intermediate between those born in the home country in the two countries. Sizeable significantly raised risks in the New Zealand-born in New Zealand compared with English and Welsh natives in England and Wales also occurred for cancers of the mouth, small intestine, colon, thymus, eye and thyroid, and non-Hodgkin''s lymphoma in each sex, and for cancer of the prostate. For all of these sites except mouth, small intestine and colon there were also risks around or above New Zealand-born levels for English and Welsh migrants to New Zealand; for colon cancer these migrants had risks close to those in England and Wales. New Zealand migrants to England and Wales had risks of cancers of the colon and prostate that were similar to or above New Zealand levels. Risks of cancers of the stomach, lung, pleura and bladder, and Hodgkin''s disease in each sex, and cancers of the cervix, ovary and scrotum and penis, were substantially and significantly lower in the New Zealand-born living in New Zealand than in English and Welsh natives in England and Wales. In English and Welsh migrants to New Zealand risks of bladder cancer in each sex, and of scrotal and penile and pleural cancer in males, approximated to England and Wales risks; cervical cancer risk approximated to the New Zealand risk; and stomach, lung and ovarian cancers showed intermediate risks. Migrants from New Zealand to England and Wales did not gain the lung cancer or clearly the stomach cancer risk of their host country, but did have bladder cancer risks approximating to those in England and Wales.(ABSTRACT TRUNCATED AT 400 WORDS)     

Time trends and occupational differences in cancer of the testis in New Zealand

The findings are reported from a New Zealand Cancer Registry-based case-control study involving 427 male patients with testicular cancer registered during the period 1979-1983 and aged 20 years or more at time of registration. Controls were also males chosen from the Cancer Registry with two controls per case, matched on age and year of registration. It was found that, as in other countries, persons in the upper social class groupings were at increased risk of testicular cancer. Persons in professional occupations were also at increased risk, but the odds ratio of 1.09 was much smaller than found in other studies. The previously reported excess risks for farmers, food and beverage workers, forestry workers, and pulp and paper workers were not supported by the New Zealand data. On the other hand, the previously reported excess risk for sales and service workers including members of the armed forces was supported, to some extent, by the New Zealand data with odds ratios of 1.38 (95% confidence limits 0.98-1.93) and 2.15 (95% confidence limits 0.80-5.79), respectively. Other groups with elevated risk include: physicians (odds ratio = 6.50, 95% confidence limits 1.29-32.6); production supervisors (odds ratio = 2.85,95% confidence limits 1.00-8.13); and motor vehicle mechanics (odds ratio = 2.02, 95% confidence limits 0.93-4.42). However, the New Zealand data generally does not suggest that occupational factors (or lifestyle factors associated with occupation) are of major direct importance in the etiology of testicular cancer. The incidence of testicular cancer has a bimodal age distribution in New Zealand and has risen markedly during the period 1948-1979. The New Zealand data differed from patterns observed in other countries in that the relative increase was approximately uniform across age groups rather than being stronger in the younger age groups.     

Maternal Resveratrol Treatment Reduces the Risk of Mammary Carcinogenesis in Female Offspring Prenatally Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) presents adverse effects on breast development/carcinogenesis. This study aimed to identify the ability of resveratrol (Res) to modify the adverse effects of TCDD in a female offspring. Pregnant female Wistar rats were allocated into four groups: TCDD, TCDD + Res, Res, and control. TCDD (1 μg/kg) was orally administered as a single dose on gestational day (GD) 15, and Res was orally administered during GD10–21 and lactation at a dose of 20 mg/kg/day. Female offsprings were euthanized on a specific postnatal day (PND) for hormonal analysis (PND 22, 48–51), vaginal opening (PND 30–48), and mammary gland morphology (PND 22). Other females received two doses of N-nitroso-N-methylurea (MNU, 50 mg/kg) on PNDs 22 and 51 and were euthanized on PND 24 (Ki-67, ER-α and apoptosis indexes or molecular analysis) or PND 180 (tumor assay). TCDD exposure altered the development of the mammary structure while these alterations were partially improved by maternal Res. Two days after first MNU administration, some genes associated with apoptosis were altered in the mammary tissue from the TCDD group (Bax and Caspase 3 down- and Bcl-2 upregulated) but were also partially reestablished by maternal Res. Mammary gland bcl-2 and bcl-xl proteins expression was increased while the apoptosis index was reduced by TCDD exposure but restored by maternal Res. An increase in number of mammary tumors was observed in female offspring from the TCDD group compared to the other groups. The results indicate that most mammary changes induced in female offspring through TCDD exposure or after MNU administrations were reduced by maternal resveratrol treatment.     

Pesticide use and colorectal cancer risk in the Agricultural Health Study

We investigated the relationship between agricultural pesticides and colorectal cancer incidence in the Agricultural Health Study. A total of 56,813 pesticide applicators with no prior history of colorectal cancer were included in this analysis. Detailed pesticide exposure and other information were obtained from self-administered questionnaires completed at the time of enrollment (1993-1997). Cancer incidence was determined through population-based cancer registries from enrollment through December 31, 2002. A total of 305 incident colorectal cancers (212 colon, 93 rectum) were diagnosed during the study period, 1993-2002. Although most of the 50 pesticides studied were not associated with colorectal cancer risk, chlorpyrifos use showed significant exposure response trend (p for trend = 0.008) for rectal cancer, rising to a 2.7-fold (95% confidence interval: 1.2-6.4) increased risk in the highest exposure category. Aldicarb was associated with a significantly increased risk of colon cancer (p for trend = 0.001), based on a small number of exposed cases, with the highest exposure category resulting in a 4.1-fold increased risk (95% confidence interval: 1.3-12.8). In contrast, dichlorophenoxyacetic acid showed a significant inverse association with colon cancer but the association was not monotonic. Our findings should be interpreted cautiously since the literature suggesting that pesticides are related to colorectal cancer is limited. Nonetheless the possibility of an association between exposure to certain pesticides and incidence of colorectal cancer among pesticide applicators deserves further evaluation.     

Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells

The aryl hydrocarbon receptor (AhR) mediates the carcinogenicityof a family of environmental contaminants, the most potent being2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increased incidenceof lymphoma and leukemia in humans is associated with TCDD exposure.Although AhR activation by TCDD has profound effects on theimmune system, precise cellular and molecular mechanisms haveyet to be determined. These studies tested the hypothesis thatalteration of marrow populations following treatment of micewith TCDD is due to an effect on hematopoietic stem cells (HSCs).Treatment with TCDD resulted in an increased number and proliferationof bone marrow (BM) populations enriched for HSCs. There wasa time-dependent decrease in B-lineage cells with a concomitantincrease in myeloid populations. The decrease in the B-celllineage colony-forming unit-preB progenitors along with a transientincrease in myeloid progenitors were consistent with a skewingof lineage development from lymphoid to myeloid populations.However, HSCs from TCDD-treated mice exhibited diminished capacityto reconstitute and home to marrow of irradiated recipients.AhR messenger RNA was expressed in progenitor subsets but isdownregulated during HSC proliferation. This result was consistentwith the lack of response following the exposure of 5-fluorouracil-treatedmice to TCDD. The direct exposure of cultured BM cells to TCDDinhibited the growth of immature hematopoietic progenitor cells,but not more mature lineage-restricted progenitors. Overall,these data are consistent with the hypothesis that TCDD, throughAhR activation, alters the ability of HSCs to respond appropriatelyto signals within the marrow microenvironment. Abbreviations: AhR, aryl hydrocarbon receptor; AhR-KO, AhR null-allele; Arnt, aryl hydrocarbon receptor nuclear translocation; BM, bone marrow; BrdU, bromodeoxyuridine; CFU, colony-forming unit; CFU-S, colony-forming unit-spleen; 5-FU, 5-fluorouracil; HPP-CFC, high proliferative potential colony-forming cell; HSC, hematopoietic stem cell; IL, interleukin; LSK, Lin^–/Sca-1⁺/cKit⁺; mRNA, messenger RNA; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin Received June 6, 2008; revised August 18, 2008; accepted September 19, 2008.     

Organ-specific effects of long term feeding of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,7,8-pentachlorodibenzo-p-dioxin on I-compounds in hepatic and renal DNA of female Sprague-Dawley rats

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potenthepatocarcinogen, and 1,2,3,7,8-pentachlorodibenzo-p-dioxin(PCDD) on liver and kidney DNA of female Sprague-Dawley ratswere investigated by ³²P-post-labeling assay. The compoundswere administered by gavage [1 µg/kg/week in corn oil(5 ml/kg)] to the animals for up to 6 months. No exposure-related³²P-labeled spots indicative of TCDDor PCDD covalent DNA adductswere noted on the chromatograms of kidney or liver DNA nucleotidesfrom the rats exposed to the toxins for 2 and 6 months. Corn-oiltreated control animals exhibited the characteristic tissue-and age-specific patterns of ³²P-labeled I-spots in liver andkidney DNA which are associated with specific DNA modificationsof unknown origin and function. Treatment with either TCDD orPCDD resulted in a substantial reduction of the levels of I-compoundsin liver, a target organ for TCDD carcinogenesis. After 6 monthsof exposure to TCDD the reductions in the amounts of individualhepatic I-compounds ranged from 37 to 77% and decreased levelswere also observed after 2 months of treatment. It was apparentthat PCDD was not as effective as TCDD in reducing hepatic I-compoundlevels and this corresponded with the lower aryl hydrocarbonreceptor binding activity of the former compound. In contrast,TCDD and PCDD did not cause any significant decrease of I-compoundsin the kidney which is not a site of TCDD-mediated carcinogenicityin female Sprague-Dawley rats. Whether I-compound deficiencycontributes to TCDD mediated hepatocarcinogenesis (e.g. by facilitatingDNA replication) needs to be investigated.     

t(14;18) translocations in lymphocytes of healthy dioxin-exposed individuals from Seveso, Italy

Dioxin exposure has been associated with non-Hodgkin's lymphoma (NHL) in epidemiological investigations. The NHL-related t(14;18) translocations can be detected at a low copy number in lymphocytes from healthy subjects. Exposure to NHL-associated carcinogens, such as dioxin or pesticides, may cause expansion of t(14;18)-positive clones. We investigated prevalence and frequency of circulating t(14;18)-positive lymphocytes in 144 healthy subjects from a population exposed to dioxin [plasma TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) range: <1.7-475.0 parts per trillion (p.p.t.)] after the Seveso, Italy, accident of 1976. t(14;18) translocations were measured in DNA from peripheral blood lymphocytes by high-sensitivity real-time quantitative polymerase chain reaction. We found that the frequency, but not the prevalence, of t(14;18) translocation-positive cells increased with increasing plasma TCDD. Among t(14;18)-positive subjects (n = 50;34.7%), the mean number of t(14;18) translocations/10(6) lymphocytes was 4.2 [95% confidence interval (CI), 2.9-6.2] in subjects with plasma TCDD < 10.0 p.p.t., 8.1 (95% CI, 4.9-13.3) in subjects with plasma TCDD between 10.0 and 50.0 and 12.5 (95% CI, 7.4-21.1) in subjects with plasma TCDD between 50.0 and 475.0 p.p.t. (P-trend = 0.003). As expected, t(14;18) frequency was associated with cigarette smoking and was highest in subjects who smoked for > or =16 years (mean = 12.6; 95% CI, 7.4-21.3; P = 0.01). Higher t(14;18) prevalence was found among individuals with fair hair color (P = 0.01) and light eye color (P = 0.04). No significant association between t(14;18)-and age was found. Our results show that dioxin exposure is associated with increased number of circulating t(14;18) positive cells. Whether this change in t(14;18) frequency is an indicator of elevated lymphoma risk remains speculative and needs further investigation for its potential impact on public health.     

Inhibition of postconfluent focus production in cultures of MCF-7 human breast cancer cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Summary 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent inducer of differentiation and an antiestrogen, is shown to suppressin vitro postconfluent cell accumulation in the estrogen-dependent MCF-7 human breast tumor cell line. This dose-responsive suppression is apparent by 14 days of exposure with an EC₅₀ between 10^–10 and 10^–11 M TCDD, and is characterized by reduced cell density (approximately 60% of controls after 14 days). This was attributed to a reduced formation in TCDD-treated cultures of multicellular foci which are chracteristic of cancer cell growthin vitro (less than 1/mm² compared to control levels of 40/mm²). Preconfluent cell growth and viability of MCF-7 cells is not affected by 10^–9 M TCDD. These results suggest that the principle of TCDD's activity may be useful in the study and possibly the management of estrogen-dependent breast tumors.     

A follow-up study of cancer incidence among workers in manufacture of phenoxy herbicides in Denmark

The purpose of this cohort study is to shed further light on the potential carcinogenic effect indicated by a Swedish case control study of the 2,4-dichlorophenol and 4-chloro-ortho-cresol based phenoxy herbicides, unlikely to be contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). In the present study it was the intention to include all persons employed in manufacture of phenoxy herbicides in Denmark before 1982. The predominant product was MCPA and only a very limited amount of 2,4,5-T was processed in one of the two factories included in the study. Registration of the cohort was based on company records, supplemented with data from a public pension scheme from 1964 onwards. Ninety-nine percent of registered employees could be followed up. Cancer cases were identified by linkage with the National Cancer Register. Totals of 3,390 males and 1,069 females were included in the study. In the analysis special attention was given to soft tissue sarcomas (STS) and malignant lymphomas (ML) which are the diagnostic groups indicated to be associated with exposure to phenoxy herbicides in the Swedish studies. Five cases of STS were observed among male employees in contrast to 1.84 expected cases. This result supports the Swedish observation of an increased risk of STS following exposure to phenoxy herbicides unlikely to be contaminated with 2,3,7,8-TCDD. However, several potential biases have to be taken into account in interpretation of this observation and these are discussed. Seven cases of ML were observed among male employees in contrast to 5.37 expected which does not support the Swedish observation of an excess risk. The total cancer risk among persons employed in manufacture and packaging of phenoxy herbicides was equivalent to the cancer risk in the Danish population. Among males thus employed 11 lung cancer cases were observed in contrast to 5.33 expected. Attention should be given to exposure to spray dried MCPA-sodium salt in the plants, but other work place exposures and tobacco consumption may have contributed to the increased risk. The tabulation of data by many diagnostic groups may explain the excesses observed for rectum cancer among males and cervical cancer among females. The study has revealed that several potential biases have to be taken into account when the Swedish observations are tested in other settings.     

Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk

Previous research demonstrates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage (e.g. chromosomal aberrations) with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide exposure and 324 single-nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1444 male controls in a nested case-control study of white Agricultural Health Study pesticide applicators. We determined interaction P values using likelihood ratio tests from logistic regression models and three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score. We adjusted for multiple comparisons using the false discovery rate (FDR) method. Of the 17 interactions that met FDR <0.2, 3 displayed a monotonic increase in prostate cancer risk with increasing exposure in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.65-5.39; P(interact) = 3.6 × 10(-4); FDR-adjusted P = 0.11]. Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r(2) = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31-3.10 for rs11744596; P(interact) = 7.2 × 10(-4); FDR-adjusted P = 0.09). In contrast, we did not observe associations among men with other genotypes at these loci. While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk.     

Characterization of the promotion of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the female rat.

Previous studies have suggested that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) acts as a promoting agent in various organ systems including the rat liver. Since a major characteristic of the stage of tumor promotion is its operational reversibility, we have assessed whether TCDD-induced promotion is reversible in a two-stage model of hepatocarcinogenesis. In this model, female Fischer F344 rats were administered a single, intragastric dose of the initiating agent, diethylnitrosamine (DEN, 10 mg/kg), at the peak of proliferation induced by a partial hepatectomy. TCDD was then administered biweekly (0.14 micrograms/kg, s.c.) for 1, 3 or 5 months. One group of animals was killed at each of these time points, while a second group was maintained for each time point for an additional 6 months in the absence of further TCDD. Four serial frozen sections of liver were each stained with a different enzyme marker of altered hepatic foci (AHF). The AHF were identified and the number and volume fraction determined by quantitative stereology. Exposure to TCDD resulted in an increase in the number and size of AHF in the initiated relative to the uninitiated rats. Increasing the duration of promotion with TCDD led to an increase in the number of AHF per liver, the volume fraction of the liver occupied by AHF and the number of markers expressed aberrantly by a single AHF. Discontinuation of TCDD administration for 6 months before killing the animals resulted in a decrease in the total number of AHF observed, but those AHF that remained increased in size with an overall increase in volume fraction of AHF. Analysis of the size class distribution for AHF for each of the periods of TCDD promotion revealed an increase in the larger AHF but a decrease in the smaller, thereby resulting in an overall decrease in number of AHF with an increase in the volume fraction of AHF. Increasing the duration of the TCDD exposure prior to its withdrawal led to an increased AHF size, phenotypic complexity and number of AHF remaining after cessation of TCDD administration. Although the levels of TCDD in livers of rats 6 months after cessation of TCDD administration were still greater than background, they were markedly reduced compared to immediately after administration. Thus, cessation of exposure to TCDD after a brief duration led to a reversal of its promotional effects on the majority of AHF, while prolonged exposure led to maintained promotion of a minority of AHF.