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International cancer agency's latest report raises concerns: WASHINGTON, Oct. 25, 2016 - The International Agency for Research on Cancer's latest report, which looks at the cancer-causing potential of five chemicals, received swift criticism from the group that represents U.S. pesticide manufacturers. IARC published a summary in The Lancet yesterday of its review of pentachlorophenol (PCP), 2,4,6-trichlorophenol (TCP), aldrin, dieldrin, and 3,3′,4,4′-tetrachloroazobenzene (TCAB). The first four have been used as pesticides, but are no longer registered by EPA. TCAB “is formed during the production and degradation of chloroanilide herbicides,” the Lancet news item said. IARC categorized dieldrin, aldrin and TCAB as “probably carcinogenic to humans” (Group 2A in its classification framework); pentachlorophenol as “carcinogenic to humans” (Group 1), and TCP as “possibly carcinogenic to humans” (Group 2B). But CropLife America, a frequent critic of the World Health Organization agency, raised questions about the report shortly after it appeared. CLA's Janet Collins, senior vice president of science and regulatory affairs, said IARC had failed to put its findings in the proper perspective. “When communicating with the general public about any potential health concerns in its environment, it is important that organizations characterize hazard with perspective regarding actual exposure and real human health risk, which IARC's communication in Lancet fails to do,” Collins said in a statement posted on CLA's website. In an interview today, Collins elaborated on that position, but also questioned why IARC even evaluated the chemicals in the first place. All uses of aldrin and dieldrin in the United States, for example, have been banned since 1987. “It begs the question: Why is IARC wasting time and resources and writing a press release?” Collins asked. “Our question continues to be: Why are we doing this?” Pentachlorophenol “has been widely used as a wood preservative and insecticide, but its production and use are now restricted,” IARC said in The Lancet. “General population exposure can occur from treated wood products, contaminated food and water, and incinerator emissions.” CropLife has been particularly outspoken in its criticism of IARC since March 2015, when the agency released a monograph - the official record of its working groups' deliberations - concluding that glyphosate, the active ingredient in Roundup, is probably a human carcinogen. A spokeswoman for CLA said Collins wants to be clear that CLA's concerns are about IARC's monograph program, not about IARC itself. The IARC report triggered a wave of regulatory reviews around the world, most of which found it was unlikely to cause cancer in humans. An EPA Scientific Advisory Panel (SAP) was originally supposed to meet last week to review an agency paper that found glyphosate is not likely to be carcinogenic, but one of the panel members withdrew, and now EPA hopes to reschedule the meeting for December. Attempts to reach IARC for comment on Tuesday were not successful. In another development concerning IARC and glyphosate, House Science Committee Chairman Lamar Smith, R-Texas, told EPA Administrator Gina McCarthy he “is concerned that the EPA will not evaluate glyphosate based on sound science.” In a letter, Smith cited documents the committee obtained that appear to contradict McCarthy's testimony to the committee about the extent of EPA involvement in the IARC glyphosate review. “From documents it has obtained, the committee has determined unequivocally” that two EPA employees, Peter P. Egeghy in the Office of Research and Development (ORD), and Matthew T. Martin of ORD's National Center for Computational Toxicology, “played a much larger role in the IARC's assessment of glyphosate than you or any EPA official has previously admitted to the committee,” Smith said. He asked McCarthy to make those two employees, as well as Jim Jones, assistant administrator for the Office of Chemical Safety and Pollution Prevention, available for interviews no later than 5 p.m. on Nov. 1. Smith also raised questions about the inclusion on the glyphosate SAP of Kenneth Portier, an American Cancer Society statistician and the brother of toxicologist Christopher Portier, who participated in IARC's glyphosate report. Did you know Agri-Pulse subscribers get our Daily Harvest email and Daybreak audio Monday through Friday mornings, a 16-page newsletter on Wednesdays, and access to premium content on our ag and rural policy website? Sign up for your four-week free trial Agri-Pulse subscription. Christopher Portier contacted Jones after EPA's initial Cancer Assessment Review Committee (CARC) report on glyphosate was accidentally posted online in May. That report, which was online for a few days before being removed, concluded glyphosate was not likely to be a human carcinogen. On May 4, 2016, Portier forwarded Jones a Politico article reporting on the posting of the CARC study “and the implications it may have for a European Union decision on glyphosate,” Smith said in his letter. “Understanding Portier's urgency in the matter, … Jones forwarded Portier's email on to his EPA subordinates stating, ‘We need to think about a statement that goes beyond saying our assessment is not final. Looks like it will be used to inform other government decisions.' “Given Portier's apparent efforts to use IARC to influence global policy decisions and his desire to discredit the (European Food Safety Authority) glyphosate study, it is reasonable to assume that Assistant Administrator Jones acted to assist him and IARC by publically (sic) downplaying scientific analysis conducted by EPA,” Smith said. Also on Tuesday, Reuters reported that IARC officials were discouraging members of its glyphosate panel from releasing documents related to the glyphosate review. IARC “does not encourage participants to retain working drafts or documents after the monograph has been published,” according to an email from IARC's Kate Guyton to six members of the glyphosate panel, Reuters reported. +++++ ----------------------------------------------------------------------------------------------- ++++ In October, 2016, 18 scientists from eight countries met at the International Agency for Research on Cancer (IARC; Lyon, France) to finalise their critical review and evaluation of the carcinogenicity of pentachlorophenol (PCP), 2,4,6-trichlorophenol (TCP), aldrin, dieldrin, and 3,3′,4,4′-tetrachloroazobenzene (TCAB) following the procedures outlined in the IARC Monographs Preamble. These assessments will be published as volume 117 of the IARC Monographs.1 +++++ ----------------------------------------------------------------------------------------------- ++++ In October, 2016, 18 scientists from eight countries met at the International Agency for Research on Cancer (IARC; Lyon, France) to finalise their critical review and evaluation of the carcinogenicity of pentachlorophenol (PCP), 2,4,6-trichlorophenol (TCP), aldrin, dieldrin, and 3,3′,4,4′-tetrachloroazobenzene (TCAB) following the procedures outlined in the IARC Monographs Preamble. These assessments will be published as volume 117 of the IARC Monographs.1 The insecticide PCP, classified as a persistent organic pollutant under the Stockholm Convention, was evaluated as “carcinogenic to humans” (Group 1). PCP has been widely used as a wood preservative and insecticide, but its production and use are now restricted. General population exposure can occur from treated wood products, contaminated food and water, and incinerator emissions. Epidemiological data provided sufficient evidence in humans for the carcinogenicity of PCP. In all of the available epidemiological studies, exposure to PCP was associated with an increased risk of non-Hodgkin lymphoma. Results from a large cohort study2 of Canadian sawmill workers showed a significant increase in the incidence of non-Hodgkin lymphoma with cumulative exposure to PCP. Significantly increased risk of non-Hodgkin lymphoma was also reported for a cohort of US pesticide manufacturing workers exposed to PCP,3 and results from two smaller studies4, 5 including pesticide manufacturing workers showed positive associations between exposure to PCP and non-Hodgkin lymphoma. Positive associations with non-Hodgkin lymphoma were also seen in three case-control studies in Sweden and New Zealand. Risk of multiple myeloma, now classified as a subtype of non-Hodgkin lymphoma, was also increased in several studies. The pattern of excess cancers differed from that observed in populations that are highly exposed to dioxins, which are possible impurities of PCP. Additionally, there was sufficient evidence of carcinogenicity in experimental animals, with a pattern of tumours that was similar across three test agents of different purity (90·4%, 91%, or ≥98% PCP). Similarly, test agents varying in purity induced mechanistic effects that are different from those exhibited by dioxins. These mechanistic studies provided strong evidence of multiple key characteristics of human carcinogens,6 indicating that PCP is metabolically activated to electrophilic benzoquinones and redox-cycling semiquinones, induces oxidative stress, is genotoxic, is anti-estrogenic, and alters cell signalling, apoptosis, and proliferation. TCP has also been used as a wood preservative, insecticide, and in the synthesis of some fungicides. The epidemiological data on TCP carcinogenicity were inadequate. There was sufficient evidence in experimental animals for the carcinogenicity of TCP, as induction of hepatocellular tumours in male and female mice, and monocytic leukaemia in male rats, has been reported.7 Few mechanistic data or other relevant data were available. TCP was evaluated as “possibly carcinogenic to humans” (Group 2B). Aldrin and dieldrin are synthetic organochlorine pesticides classified as persistent organic pollutants under the Stockholm Convention. Their use in several countries has been banned or severely restricted since the early 1970s, and general population exposures have declined. There was sufficient evidence in experimental animals for the carcinogenicity of aldrin, with three studies8, 9, 10reporting the induction of hepatocellular carcinomas. Epidemiological data on aldrin were inadequate and mechanistic data were sparse. However, since aldrin rapidly converts to dieldrin in the body, exposure to aldrin inevitably entails internal exposure to dieldrin. Dieldin is slowly excreted in humans because of inefficient metabolism and sequestration in fat. For dieldrin, a prospective study in Denmark found a significant increase in the risk of breast cancer with increasing serum dieldrin levels.11 A similar study in Norway did not find an association, but had fewer exposed cases. Positive associations with breast cancer were also reported in wives of men who had used dieldrin in the US Agricultural Health Study12 and in women with the highest level of serum dieldrin in a case-control study in Long Island (NY, USA).13 https://www.ncbi.nlm.nih.gov/pubmed/12163320?dopt=Abstract http://cebp.aacrjournals.org/content/11/8/686.long There was limited evidence in humans on dieldrin for breast cancer, and inadequate evidence for non-Hodgkin lymphoma and other cancers. There was sufficient evidence in experimental animals for the carcinogenicity of dieldrin, as hepatocellular carcinoma was observed in male and female mice in most of the 15 available studies.8, 9, 10 Mechanistic studies provided moderate evidence for multiple key characteristics of carcinogens. Dieldrin, and aldrin metabolised to dieldrin, was evaluated as “probably carcinogenic to humans” (Group 2A). TCAB is not manufactured commercially but is formed during the production and degradation of chloroanilide herbicides such as propanil, linuron, and diuron. TCAB was detected in propanil formulations (up to 2600 μg/g)14 and in soil 2 years after propanil application. No exposure measurements were available, but exposure to TCAB can occur in herbicide manufacturing or application, from residues on food, or via proximity to aniline herbicide applications. No epidemiological studies of the carcinogenicity of TCAB were identified. Chloracne, a response pathognomonic for aryl hydrocarbon receptor (AhR) activation, was reported in four case series of workers exposed to TCAB and other chemicals during dichloroaniline herbicide production. TCAB bears structural resemblance to dioxins and is highly lipophilic, but is rapidly metabolised, with extensive azo reduction in the gut and liver to give 3,4-dichloroaniline metabolites that are readily eliminated. In mice and rats, the incidence of multiple tumour types was increased, providing sufficient evidence in experimental animals for the carcinogenicity of TCAB. Lung tumours occurred in mice and rats. In mice, TCAB also caused cancers of the urethra and forestomach, fibrosarcomas and malignant schwannomas of the skin, and lymphomas. In rats, TCAB also induced malignant schwannoma, and cancers of the biliary system and oral mucosa.15 This spectrum of rodent tumours encompasses those observed with other AhR agonists previously evaluated as Group 1 carcinogens (eg, dioxins, dioxin-like polychlorinated biphenyls, and 2,3,4,7,8-pentachlorodibenzofuran). Additionally, TCAB induces multiple non-neoplastic effects in rodents, rabbits, chicken, and zebrafish that are consistent with, or are hallmarks of, AhR activation. Specifically, in mice and rabbits, TCAB causes chloracne, and in chronically exposed rodents, TCAB induces CYP1A1 and CYP1A2, wasting syndrome, thymic atrophy, as well as hyperplasia and chronic inflammation in multiple tissues.15TCAB activates AhR in rats, mice, and chicken embryos; in vitro, TCAB binds to mouse AhR, and activates rat and rainbow trout AhR.15, 16, 17, 18 These mechanistic data provided strong evidence that TCAB modulates receptor-mediated effects, induces chronic inflammation, and alters cell proliferation. TCAB was classified as “probably carcinogenic to humans” (Group 2A) because it belongs, on the basis of mechanistic considerations, to a class of agents that activate AhR, and some members of this class have previously been evaluated as Group 1 or Group 2A carcinogens. +++++ ----------------------------------------------------------------------------------------------- ++++ http://link.springer.com/article/10.1007%2Fs10552-006-0007-9 Cancer and Occupational Exposure to Pentachlorophenol and Tetrachlorophenol Objective The objective of this study is to assess the carcinogenicity of pentachlorophenol and tetrachlorophenol using data from the BC sawmill workers cohort study.
Methods The cohort consisted of 27,464 men employed by 14 sawmills for 1 year or more between 1950 and 1995. Fatal (1950–1995) and incident (1969–1995) cancers were identified using national registries. Plant records and systematic interviews with senior employees were used to estimate dermal exposure. Comparisons were made with the general BC population and dose-response relationships were assessed using Poisson regression. Results There were 1,495 fatal cancer and 2,571 incident cancers. There were no large or statistically significant excesses of any of the specific cancers were observed compared to the general population. Internal analyses showed strong dose-response relationships for non-Hodgkin’s lymphoma, multiple myeloma, and kidney cancer. These relationships were strongest when exposure was restricted to pentachlorophenol. The strength of the dose-response increased when exposure was lagged by 20 years.
Conclusions Dermal exposure to pentachlorophenol was associated with non-Hodgkin’s lymphoma, multiple myeloma, and kidney cancer, but not with other cancers of a priori interest. +++++ ----------------------------------------------------------------------------------------------- ++++ http://www.sciencedirect.com/science/article/pii/S0045653511002281 Mortality of US pentachlorophenol production workers through 2005 Abstract A cohort of 2122 US pentachlorophenol (PCP) production workers from four plants in the National Institute for Occupational Safety and Health Dioxin Registry was exposed to PCP and to polychlorinated dibenzo-p-dioxin and dibenzofuran contaminants of PCP production. A subcohort of 720 was also exposed to 2,3,7,8-tetrachlorodibenzodioxin, a contaminant of trichlorophenol (TCP) while using TCP or a TCP derivative. PCP and several production contaminants have been implicated as animal carcinogens. A priori hypotheses were that the cohort would have elevated standardized mortality ratios (SMRs) for aplastic anemia, soft-tissue sarcoma, and non-Hodgkin lymphoma, as suggested by human studies, and for leukemia and liver, adrenal, thyroid, and parathyroid cancer, as suggested by animal studies. From 1940 to 2005 1165 deaths occurred with an overall SMR of 1.01 [95% confidence limits (CI), 0.95–1.07]. Overall cancer mortality (326 deaths, SMR 1.17, CI 1.05–1.31) was in statistically significant excess. There were excess deaths for trachea, bronchus and lung cancers (126 deaths, SMR 1.36, CI 1.13–1.62), non-Hodgkin lymphoma (17 deaths, SMR 1.77, CI 1.03–2.84), chronic obstructive pulmonary disease (63 deaths, SMR 1.38, CI 1.06–1.77), and medical complications (5 deaths, SMR 3.52, CI 1.14–8.22). In race- and sex-specific analyses, white males had increased non-Hodgkin lymphoma mortality (17 deaths, SMR 1.98, CI 1.15–3.17) and males of other races had increased leukemia mortality (four deaths, SMR 4.57, CI 1.25–11.7). The excess of cancers of a priori interest, non-Hodgkin lymphoma and leukemia, provide some support for the carcinogenicity of PCP, however, further studies with more detailed exposure assessment are needed. Highlights ► All 2122 former US pentachlorophenol (PCP) production workers were studied. ► Evidence suggests that PCP and some production contaminants are animal carcinogens. ► A mortality analysis compared PCP workers to the US population. ► Overall cancer mortality was in statistically significant excess. ► Lung cancer and non-Hodgkin lymphoma mortality were significantly increased.
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