Environmental Chemicals and Cancer Clusters: Cause and Effect, or Coincidence?

Environmental chemicals and Cancer clusters: Cause and effect, or coincidence? Two examples (1 cause-and-effect; 1 [almost certainly] coincidence): 1. Vinyl chloride at B.F. Goodrich plant, Louisville, Kentucky and liver cancer (angiosarcoma of the liver) 2. Trichloroethylene in East Woburn, MA, and childhood leukemia (as in, A Civil Action) How / why are people exposed to vinyl chloride? Vinyl chloride (monomer) is polymerized to make polyvinyl chloride (PVC) polymer. Commercial production began in the 1930's. Worldwide production is enormous: currently - 18 million tons annually. RAW MATERIALS Salt Hydrocarbons & Oil Electricity Electrolysis Cell Chlorine Gas 'Cracker' Ethylene Gas Natural Gas VCM Plant VCM Gas Hydrochloric Acid PVC Plant PVC Blender Products Figure by MIT OCW. Caustic Soda Hydrogen Gas Properties of vinyl chloride: Colorless gas; sweet odor. No obvious acute toxicity from early occupational exposures. Early occupational guideline for allowable exposures (pre-OSHA): 1961: American Council of Government and Industrial Hygienists (ACGIH): TLV of 500 parts per million (ppm, v/v), 8-hr. TWA. Basis? Research at Dow Chemical (Torkelson et al., 1961): rodents develop liver and kidney toxicity following exposure to 500 ppm; NOAEL = 50 ppm. Recommend reduction in TLV to 50 ppm. Little action taken. Mid-1960's: Acroosteolysis appears in some Goodrich workers (bone erosion at fingertips). Noticed by plant’s occupational physician, John Creech, M.D. (1967). Workers were screened and their hands x-rayed. Some changes made in work procedures (at least at Goodrich) to reduce exposures. Cancer case reports: 1971: one BF Goodrich (Louisville, KY) VCM worker dies of angiosarcoma of the liver (ASL; rare form of cancer: only about 25 cases per year in U.S. expected). 1973: a second BF Goodrich worker dies of ASL, and another worker is diagnosed with ASL. Search of company death certificates: a 4th case may have occurred in 1968. (Creech and Johnson [Goodrich’s company docs], 1974). Total workforce at this plant - 300. Case reports of Angiosarcoma of the Liver among Polyvinyl Chloride Workers B.F. Goodrich Plant, Louisville, Kentucky Dates of: Case Age at illness onset Illness onset Diagnosis Death Years worked with vinyl chloride before illness 1 43 Aug. 1967 Sept. 1967 Jan. 7, 1968 17 2 36 Jan. 1970 May 1970 Sept. 27, 1971 14 3 41 Jan. 1964 Mar. 1973 Mar. 3, 1973 14 4 58 July 1973 Dec. 1973 Dec. 19, 1973 27 Bioassays in lab rodents (Italian researchers): Rats exposed to 30,000 ppm VCM develop various tumors (but not ASL: Viola; 1971). Rats, mice, and hamsters exposed to VCM all develop some ASL and other tumors (Maltoni, early-mid-1970's) Rat exposure-response data (Maltoni, 1977)* Number of Animals with Tumors Groups Concentration of vinyl chloride, ppm No. of Animals (Sprague-Dawley rats) I 200 II Liver Angiosarcomas Nephroblastomas 120 12 3 150 120 5 7 III 100 120 1 10 IV controls 120 0 0 *Exposure by inhalation to vinyl chloride in air, at 200, 150, 100 ppm. 4 hr/day, 5 days/week, for 52 weeks (half-lifetime). (Results after 143 weeks = end of the experiments.) Regulatory responses Spring 1974: OSHA PEL (which had been 500 ppm) reduced to an “emergency temporary standard” (ETS) of 50 ppm, and extensive air monitoring and respiratory protection mandated; ETS superseded within months (January 1, 1975) by a permanent standard of 1 ppm. Industry responses: Ruling challenged in court -- claimed that PEL was infeasible and exorbitantly expensive (Court disagreed: OHSA won). But also (1) Industry sponsored proper epidemiologic studies, (2) U.S.-European VCM-ASL registry established, and (3) Industry-based process engineers quickly re-engineered (enclosed) VC reactors; “hand cleaning” of reactors eliminated; worker exposures substantially reduced. Epidemiologic studies: Early 1980's and 1990's. Wong et al. (1991). [“An industry-wide epidemiologic study of vinyl chloride workers, 1942-1982.”] Studied a cohort of 10,173 men who had worked for at least one year in jobs involving exposure to vinyl chloride prior to 1 January 1973. Men employed at 37 plants in the U.S., belonging to 17 companies. A total of 1,536 deaths: 15 deaths from angiosarcoma. Was industry too slow to respond? Or was it “just” a “different” era? May 12, 1959 Mr. W. E. McCormick, Director Department of Industrial Hygiene and Toxicology The B.F. Goodrich Company 500 South Main Street Akron, OH Dear Bill: This is in reply to your letter of May 4 inquiring about the toxicological information we might have on vinyl chloride. Insofar as I am aware, there is no good toxicological data in the literature of the chronic toxicity of vinyl chloride. As you know, the Conference of Governmental Industrial Hygienists has for some time been recommending a maximum average of 500 ppm. This figure is based upon the acute data of Patty, et al. and, hence, can not be relied upon to strongly when considering chronic exposures. Some years ago, we prepared a little writeup assuming that this figure was alright and a copy of it is enclosed to show you what we have said. I have added my comments to it for your information. I should add that in the last month we have been investigating vinyl chloride a bit and find it to be somewhat more toxic when given by repeated daily inhalations but it is too early yet to tell what vapor concentrations will be without adverse effect. We feel quite confident, however, that 500 ppm is going to produce rather appreciable injury when inhaled 7 hours a day, five days a week for an extended period. As you can appreciate, this opinion is not ready for dissemination yet and I would appreciate it if you would hold it in confidence but use it as you see fit in your own operations. When more data becomes available, I will try to remember to pass it on to you. Best regards. Sincerely yours, V.K. Rowe Biochemical Research Laboratory Inter-Company Correspondence Company: Union Carbide Company Location: Mellon Institute To: Location: Dr. T.W. Wale New York Office Date: Attention Copy To: November 24, 1959 Dr. E.R. Weidlein, Jr. Dr. A.W. Downes Dear Tom: You will recall that the current threshold limit for vinyl chloride is 500 ppm, based largely on single guinea pig inhalation studies by the Bureau of Mines about 25 years ago. An off-the-record phone call from V.K. Rowe gives me incomplete data on their current repeated inhalation study. Six months at 500, 200 and 100 ppm has not found a no-effect level. Even 100 ppm produced organ weight changes and gross pathology, with micropathology expected. Vinyl chloride monomer is more toxic than has been believed. Rowe expects to get more information before he decides whether or not this has any bearing on the safety of packaging uses of vinyl resins. Dow has been distributed at sales efforts saying chloroform is less toxic than carbon tet. They have completed six months inhalation and find chloroform like carbon tet. This means its threshold limit will be lowered, as I have suggested for years. It was originally set by analogy with carbon tet, and never lowered when that for carbon tet was reduced. I suggest that these personal communications not be quoted until Dow publishes. Very truly yours, Henry F. Smyth, Jr. What is A Civil Action about? A. Contaminated drinking water (from municipal wells); B. A (space-time) cluster of childhood cancer (“discovered” by a mom and minister); and C. The scientific question, “Did A cause B?” D. [Other questions: Are such scientific questions best answered via lawsuits? Is “justice” thereby served? Who contaminated the water? Is the cluster “statistically significant”? etc. . . ] From: Cutler JJ, Parker GS, Rosen S, Prenney B, Healey R, Caldwell GG. 1986. Childhood leukemia in Woburn, Massachusetts. Public Health Rep. 101(2):201-5. “Possible associations between environmental hazards and the occurrence of childhood leukemia were investigated in Woburn, MA, for the period 1969-79. Residents [parents and a minister] of Woburn were concerned over what they perceived to be a large number of childhood leukemia cases . . . Many believed that the elevated rate of childhood leukemia was related to . . . two city water wells that had been closed in 1979 when they were found to be contaminated by organic chemicals. . . This investigation confirmed an increase in incidence which was distributed uniformly over the 11-year period. . . . While the contaminants of Wells G and H, which had been closed, are not known leukemogens, it is not possible to rule out exposure to this water as a factor, particularly in the eastern Woburn residents.” How sizable / significant was the increased rate? (MA Cancer Registry only established in 1982). Standardized Incidence Ratios (SIRs) for Leukemia (all types) by Sex in W oburn, Massachusetts January 1969 - December 1983 Sex Number Observed Number Expected Ratio 95% Confidence Limits* Male 12 3.99 3.00 1.55, 5.25 Female 4 2.02 1.98 0.54, 5.07 Both 19 6.01 3.16 1.90, 4.93 * Fisher exact. Number of Observed and Expected Cases of Luekem ia (all types) by Census Tract in Woburn, Massachusetts January 1969 - December 1983 Number of Cases Census Tract 3331 3332 3333 3334 3335 3336 Observed 4 0 1 7 6 1 Expected 1.08 0.82 0.75 .92 1.46 1.00 Poisson Probability 0.02 --- 0.53 5.0 x 10 -5 0.004 0.74 From: Cutter (1984) Who contaminated the well water in East Woburn? Plaintiffs’ view: Map removed for copyright reasons. G and H = Wells G and H Red Dots = homes of plaintiffs (each with a case of pediatric cancer) U = Unifirst [Dry-cleaned commercial uniforms, using perc] C = Cryovac (W.R. Grace) [Manufactured food processing and packaging equipment, 1960-1988; used TCE] R = Riley Tannery [1910-1990's: property purchased by Beatrice Foods in 1978 (contamination discovered in 1979)] Who contaminated the water? Map removed for copyright reasons. U.S. EPA view: probably more complicated than this. Courtesy of U.S. Environmental Protection Agency (EPA). Woburn is an old city (incorporated 1642) 1800's: Manufacturing center, tanning leather, making shoes and boots. 1865: “Woburn was at the head of the tanning industry in the country.” 1884: 26 large tanneries operating. 1901: Henry Thayer of Woburn originates chrome (Cr VI) tanning (replaces bark tanning) By 1915: Some diversification: making ice cream, machine tools, mops, and paper boxes. 1920s: Groundwater wells for drinking water, the first in Massachusetts, began operating. [Eventually, 6 wells (A - F) drilled into the groundwater aquifer surrounding Horn Pond (south-central Woburn)] Early 1960's: Population growing, water becoming scarce: city officials consider drilling wells in groundwater-rich, swampy, industrialized East Woburn. 1964: Drinking water Well G constructed (along the east floodplain of the Aberjona River) 1967: Well H constructed. Soon thereafter, recommendations to take wells G & H out of service due to bacterial contamination: heavily chlorinated instead. Resident: “The odor is almost like a clear bleach . . . ." Early-mid 1970's: the State warns that water in Wells G & H is of poor quality, with elevated levels of nitrates, chlorides, sulfates, sodium, manganese, hardness, and elevated levels of carbon-chloroform extract [crude indication of organic contaminants] 1979: TCE and perc detected What are our sources of drinking water in Massachusetts? É Groundwater wells – public and private. É Surface water – from reservoirs or rivers. 2004 Public Drinking Water System Reliance on Ground Water and Surface Water Sources in New England Surface Water Ground Water State Population % of Population Population % of Population Connecticut 462,052 17 2,231,612 83 Massachusetts 2,065,285 43 2,709,203 57 Maine 453,058 52 417,863 48 New Hampshire 595,129 56 474,976 44 Rhode Island 209,548 28 551,162 72 Vermont 345,659 56 266,510 44 What was the primary waterborne contaminant? (What about the other contaminants, chemical and microbiological . . .?) Trichloroethylene (TCE) Colorless, volatile liquid; Versatile organic solvent Reasonably chemically stable Very low flammability: no measurable flashpoint Not very toxic acutely; Not unpleasant odor Widely used in industry (since about 1930) metal cleaning / degreasing 55 % chemical intermediate 41 % Historically, use of TCE replaced use of CCl4 and CHCl3, which had replaced use of petroleum distillates. Concentration in Woburn water . 260 :g / liter (260 ppb) U.S. EPA “Maximum Contaminant Level” (MCL) = 5 ppb. (TCE is a very common groundwater, hence drinking water, contaminant) Does gross “exceedance” of MCL mean that children (fetuses) exposed to this water developed cancer as a result? Leukemias: 4 basic types: lymphoid and myeloid (acute and chronic). All arise from cells in the bone marrow (soft inner part of some bones) Three diagrams removed for copyright reasons. What do we know about acute lymphoblastic leukemia (ALL)? The horizontal axis shows 5-year age intervals. The vertical axis shows the frequency of new cases of ALL per 100,000 in a given age group. Note that the risk of ALL is greatest in the first 5 years of life. (Data from SEER Program of the National Cancer Institute.) ALL is the most common of all pediatric cancers: . 2,000 new cases of childhood ALL diagnosed annually in U.S. Cause(s)? Unknown. Timing? “Mistakes” during fetal development? Exposures in utero? (Offspring of cigarette smoking moms: are they at excess risk of ALL?). Possible causes: Bad luck Genetic predisposition (e.g., Down syndrome) (Retro)virus(es)? (Analogy with other mammals) EMF? Woburn: contaminated drinking water??? What do we know about cancer clusters in communities? From: Caldwell GG. 1990. Twenty-two years of cancer cluster investigations at the Centers for Disease Control. Am J Epidemiol. 132(1 Suppl):S43-7: Beginning in 1961 [and spanning 20 years of investigation], the Centers for Disease Control investigated 108 cancer clusters . . . The clusters studied were of leukemia (38%), leukemia and lymphoma (30%), leukemia and other cancer combinations (13%), and all other cancer or combinations (19%). . . . Although 14 different categories of associations were reported [and despite lab tests for radiation, chemicals, viruses, and genetics], no clear cause was found for any cluster. A reminder that, in community (chronic) disease investigations, most hypotheses are wrong. Does TCE cause cancer in over-exposed factory workers? Lots of epidemiologic study of this question. Answer: Probably not. . . “limited evidence.” No “unusual” cancers. TCE not IARC “Group 1.” Overall Evaluations of Carcinogenicity to Humans (per IARC Monographs Volumes 1-88) Group 1: Carcinogenic to humans (95): (Established via sufficient epidemiologic evidence) AGENTS AND GROUPS OF AGENTS Human papillomavirus type 16 Aflatoxins Human papillomavirus type 18 Human T-cell lymphotropic virus type I 4-Aminobiphenyl Arsenic and arsenic compounds Melphalan Asbestos 8-Methoxypsoralen (Methoxsalen) plus Azathioprine ultraviolet A radiation Benzene MOPP and other combined chemotherapy including alkylating agents Benzidine Mustard gas (Sulfur mustard) Beryllium 2-Naphthylamine N,N-Bis(2-chloroethyl)-2-naphthylamine Neutrons (Chlornaphazine) Nickel compounds Bis(chloromethyl)ether and chloromethyl Opisthorchis viverrini methyl ether Oral contraceptives, combined 1,4-Butanediol dimethanesulfonate Oral contraceptives, sequential (Busulphan; Myleran) Phosphorus-32, as phosphate Cadmium and cadmium compounds Plutonium-239 and its decay products as Chlorambucil aerosols 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-ni Radioiodines, short-lived isotopes, including trosourea (Methyl-CCNU; Semustine) iodine-131, from atomic reactor accidents and Chromium[VI] compounds nuclear weapons detonation Ciclosporin Radionuclides, a-particle-emitting, internally Cyclophosphamide deposited Diethylstilboestrol Epstein-Barr virus Radionuclides, b-particle-emitting, internally deposited Erionite Radium-224 and its decay products Estrogen therapy, postmenopausal Radium-226 and its decay products Estrogens, nonsteroidal Ethylene oxide Radium-228 and its decay products Etoposide in combination with cisplatin and Radon-222 and its decay products bleomycin Schistosoma haematobium Silica crystalline Formaldehyde [Gamma Radiation: see X- and Gamma Solar radiation (g)-Radiation] Talc containing asbestiform fibres Gallium arsenide Tamoxifen Helicobacter pylori Hepatitis B virus Hepatitis C virus Herbal remedies containing plant species of the genus Aristolochia Human immunodeficiency virus type 1 Group 1: Carcinogenic to humans (95), continued: 2,3,7,8-Tetrachlorodibenzo-p-dioxin Thiotepa Thorium-232 and its decay products Treosulfan Vinyl chloride X- and Gamma (g)-Radiation MIXTURES Alcoholic beverages Analgesic mixtures containing phenacetin Areca nut Betel quid with tobacco Betel quid without tobacco Coal-tar pitches Coal-tars Mineral oils, untreated and mildly treated Salted fish (Chinese-style) Shale-oils Soots Tobacco products, smokeless Wood dust EXPOSURE CIRCU MSTANCES Aluminium production Arsenic in drinking-water Auramine, manufacture of Boot and shoe manufacture and repair Coal gasification Coke production Furniture and cabinet making Haematite mining (underground) with exposure to radon Involuntary smoking Iron and steel founding Isopropanol manufacture Magenta, manufacture of Painter (occupational exposure as a) Rubber industry Strong-inorganic-acid mists containing sulfuric acid (occupational exposure to) Tobacco smoking What about results in lab rats and mice exposed chronically to TCE? Table Doses of trichloroethylene (TCE): toxicologic and other benchmarks Endpoint TCE (mg/kg-day) Doses to people from water in Woburn ?? Worker's day-long exposure to CalOSHA PEL (25 ppm) ?? Mouse NOAEL: liver cancer (half-lifetime exposure; Herren-Freund et al., 1987) 6 Rat NOAEL: kidney cancer (one-year exposure; Maltoni et al., 1986) 250 Rat LOAEL: kidney cancer (NTP, 1988) 500 Mouse LOAEL: liver cancer (NTP, 1990) 1,000 TCE (and other solvents) elsewhere in groundwater in the U.S. 1980: Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA; ), commonly known as “Superfund” enacted: money from a tax on the chemical and petroleum industries, mandates U.S. EPA “respond directly to releases or threatened releases of hazardous substances that may endanger public health or the environment.” > 1,400 National Priorities List (NPL) sites in U.S.; TCE has been detected at some 850 of these! Per the U.S. Agency for Toxic Substances and Disease Registry (ATSDR) “Drinking or breathing high levels of trichloroethylene may cause nervous system effects, liver and lung damage, abnormal heartbeat, coma, and possibly death.” Are statements like this informative? [ATSDR’s motto: “To Protect America's Health from Toxic Exposures”] What concentration of TCE in groundwater that serves (or may serve) as drinking water is acceptably small? (Aquifer clean up = “remediation” = improving public health?) Quantitative health risk assessment for TCE: nothing (really) to do with Woburn. Based instead on results of rat/mouse bioassays, combined with massive regulatory infrastructure . . . Huge $$ at stake. TCE toxicology, mechanisms, and QRA for another time. . . For now, by next Tuesday, Feb. 15, 2005, please do the following and email to me your answers: Compare and contrast former occupational exposures to vinyl chloride in air with drinking water exposures to TCE in Woburn (and currently permissible workplace exposures to TCE). Express doses as mg/kg-day, with plausible ranges. In air, X ppm = (Y mg/m3)(24.45)/(molecular weight) In water, x ppb = x ug/L