Abstract
The United States Environmental Protection Agency’s (U.S. EPA) National Priorities List (NPL) is a list of sites in the U.S. and its territories of national priority that are sources of known hazardous contaminants, pollutants, or substances that pose a significant risk to human health and the environment. These sites are commonly termed U.S. Superfund sites and contain many harmful compounds and metals. This paper reviews the carcinogenic potential of the most frequent compounds, metals, and mixtures at U.S. Superfund sites. Of the most frequent compounds and metals identified at U.S. Superfund sites, some are classified as human carcinogens and some as probable/possible human carcinogens. The most frequent mixtures of three individual carcinogenic compound or metals at U.S. Superfund sites include: nickel, arsenic, and cadmium (496 sites); benzene, arsenic, trichloroethene (451 sites); benzene, vinyl chloride, trichloroethene (420 sites); and arsenic, vinyl chloride, trichloroethene (386 sites). Many compounds or metals that are frequently found at U.S. Superfund Sites have not been evaluated for carcinogenic activity because of limited data including copper, xylene, mercury, barium, and iron. Factors in human cancer development include both environmental factors and genetic disease susceptibility backgrounds. Thus, future mixture toxicology studies should be conducted with a design that looks at mixture toxicology in a variety of models with varied genetic backgrounds.
Introduction
Environmental exposures to compounds and metals can contribute to the development of cancer, − a leading cause of death in the U.S. Communities living near U.S. Superfund sites have the potential to be exposed to carcinogenic compounds and metals found at these sites. This paper reviews the carcinogenic potential of the compounds/metals and mixtures most frequently found at U.S. Superfund sites as reported by the National Toxicology Program (NTP) 2-year rodent bioassays technical documents, the NTP Report on Carcinogens (RoC), and the International Agency for Research on Cancer (IARC).
The United States Environmental Protection Agency (U.S. EPA) National Priorities List (NPL) is a list of sites in the U.S. and its territories of national priority that contain known hazardous contaminants, pollutants, or substances that are deemed to pose significant risk to human health and the environment. There is a continuing effort to remove hazardous compounds, metals, and mixtures from many of the over 1000 federally recognized contaminated sites in the U.S. and its territories, but it may take decades to complete the cleanup. In 1980, the U.S. Congress passed the “Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA)”, which included legislation for “long-term remedial response actions, to permanently and significantly reduce the dangers associated with releases or threats of releases of hazardous substances that are serious, but not immediately life threatening”. This act was reauthorized in 1986 and required the U.S. EPA to ensure that it assessed the relative degree of risk to human health and the environment posed by uncontrolled hazardous waste sites that may be placed on the NPL. The toxicity of not only a single compound exposure at these waste sites but also exposure to compound/metal mixtures at these sites is of concern.
Compounding the concern for exposure to toxic and carcinogenic compounds/metals/mixtures at U.S. Superfund sites are other social factors and noncompound stressors including decreased access to health care, food insecurity, and unfavorable housing conditions that may add to disease susceptibility. Prior to a 1994 Executive Order, there were biases in the cleanup of U.S. Superfund sites located in neighborhoods where vulnerable populations lived but support of cleaning up sites located in areas with an educated population.
Traditional toxicology and cancer studies are usually conducted on one compound or metal at a time, and subsequent human health evaluations are also often conducted on one compound or metal at a time. Understanding cancer hazards from mixture exposures will allow a more complete evaluation of the human health hazards from environmental exposures. Studies have shown that ∼50% of human cancers are considered due to environmental factors and ∼50%, due to genetic background. Additional studies on the cancer potential of compound and metal mixtures frequently found at U.S. Superfund sites will help in our understanding of the potential health hazards from environmental exposures.
Methodology
Compounds and Metals Identified at U.S. Superfund Sites
Using the U.S. EPA U.S. Superfund List 10, the most frequently found compounds, metals, and compound and metal mixtures at U.S. Superfund sites were analyzed to determine the cancer hazard potential of single compounds or metals and combinations (mixtures) of these compounds and metals.
Evaluation of the Cancer Potential of Compounds and Metals Found at Superfund Sites Using National Toxicology Program Data
The carcinogenic potential of compounds and compound/metal mixtures was evaluated using data from the National Toxicology Program (NTP) Report on Carcinogens (RoC). , Salmonella results were from NTP genetic toxicity tests.
The NTP RoC, which was used as a primary source for the cancer potential of the top 30 most frequently found compounds and metals uses the following cancer classification scheme , to categorize human carcinogens: “Known To Be Human Carcinogen” – there is sufficient evidence of carcinogenicity from studies in humans, which indicates a causal relationship between exposure to the agent, substance, or mixture, and human cancer; “Reasonably Anticipated To Be Human Carcinogen (RAHC)” – there is limited evidence of carcinogenicity from studies in humans, but there is sufficient evidence for cancer in animal model studies.
Additional information provided for the top 30 most frequently found compounds and metals at U.S. Superfund sites was from the NTP cancer rodent studies. The NTP rodent study conclusions included “Clear evidence of carcinogenic activity” demonstrated by studies that are interpreted as showing a dose-related (i) increase of malignant neoplasms, (ii) increase of a combination of malignant and benign neoplasms, or (iii) marked increase of benign neoplasms if there is an indication from this or other studies showing the ability of such tumors to progress to malignancy; “Some evidence of carcinogenic activity” demonstrated by studies that are interpreted as showing a compound-related increased incidence of neoplasms (malignant, benign, or combined) in which the strength of the response is less than that required for clear evidence; “Equivocal evidence of carcinogenic activity” demonstrated by studies that are interpreted as showing a marginal increase of neoplasms that may be compound related; and “No evidence of carcinogenic activity” demonstrated by studies that are interpreted as showing no compound-related increases in malignant or benign neoplasms. Inadequate study of carcinogenic activity is demonstrated by studies that, because of major qualitative or quantitative limitations, cannot be interpreted as valid for showing either the presence or the absence of carcinogenic activity. NTP Salmonella toxicity test results are added to help understand cancer mechanisms.
Evaluation of Cancer Potential Using Other Data Sets
The International Agency for Research on Cancer (IARC) cancer classifications for the most frequent U.S. Superfund compounds/metals are also provided for the top 30 most frequently found compounds and metals as additional information to the RoC cancer classifications.
The IARC Classification for carcinogens involves classification into Groups 1–3: “Group 1” – The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans; “Group 2A” – The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans; “Group 2B” (the agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans; and “Group 3” – The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.
Data Processing
The data for this project were generated through a data processing pipeline consisting of the following stages:
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(1)
Downloaded data sets of compounds and metals at U.S. Superfund sites.
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(2)
Prepared data sets (removed missing rows, relabeled columns to support merging of data sets).
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(3)
Reorganized data sets to a format with one compound and multiple findings per row. This step was necessary as reporting agencies often report findings for multiple compounds on the same row or multiple findings are reported for a compound on separate rows (typically when a compound was reported on in separate studies).
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(4)
Combined sets of similar compounds (e.g., different nickel or chromium compounds) as one set of compounds found at the U.S. Superfund sites. The compounds (e.g., nickel compounds) are treated as individual compounds in the subsequent processing steps and the individual compounds that constitute the compounds are removed. This was done for chromium(VI) compound (18540-29-9, 7789-12-0, 7778-50-9, 13007-92-6, 7775-11-3, 7778-50-9); nickel compound (1313-99-1, 12035-72-2, 7440-02-0); chromium(III) compound (16065-83-1, 27882-76-4, 14639-25-9); and arsenic compound (7778-39-4, 1327-53-3, 1303-00-0, 64436-13-1, 7440-38-2).
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(5)
Merged data sets into a combined file for analysis, dropping all compounds that do not appear in the EPA Superfund site list.
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(6)
Computed a single compound hazard score for each compound.
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(7)
Computed a mixture compound hazard score for each mixture.
CAS registry numbers were used to identify equivalent compounds across the data sets. Automated software and manual quality-assessment checks were conducted to ensure that each pipeline stage performed as described in this section, and a final set of software tests compared the hazard scores from stages 6 and 7 versus hand-computed scores for each possible set of conditions.
Results
Overview of Compounds, Metals, and Mixtures Identified at the U.S. Superfund Sites
The most frequent organic compounds and metals identified in 1582 Superfund sites are found at sites across the country. There were a total of 1042 different individual compounds/metals present in U.S. Superfund sites based on unique names with 761 unique CAS registry numbers (Supplement One). Seven hundred of the unique CAS registry numbers are valid CAS registry numbers (using the Python casregnum package). Individual CAS registry numbers may not be found for some compound classes (e.g., TBD-000000027 is the CAS number used for the class PCBs) (Supplement One).
These compounds/metals may be present in high concentrations in the soil or ground water at Superfund sites throughout the U.S. The location of many of these Superfund sites are in regions of the U.S. where there is a continuing rise in temperature and where there are various social factors of concern.
Cancer potential of individual compounds and metals was based on the NTP RoC and IARC data. The cancer potential of the 30 most frequent compounds and metals found at U.S. Superfund sites were assessed based on evaluations from the NTP RoC and IARC (Table ). The number of sites where the 30 most frequently found compounds or metals are found is summarized in Figures and .
1. Cancer Classification of Single Compounds and Metals Frequently Found at U.S. Superfund Sites.
| Cas. No. | Compound/Metal | Number of U.S. Superfund Sites | NTP Report on Carcinogens (RoC) Cancer Classification | IARC Cancer Classification | NTP Salmonella Results | NTP Technical Report Number | NTP Male Rat Cancer Target Organs | NTP Female Rat Cancer Target Organs | NTP Male Mouse Cancer Target Organs | NTP Female Mouse Cancer Target Organs |
|---|---|---|---|---|---|---|---|---|---|---|
| 7439-92-1 | Lead Compounds | 991 | Reasonably anticipated – humans – lung, stomach, and urinary-bladder cancer | Group 2A | Not evaluated | Not tested in NTP cancer studies | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| Benign and malignant kidney tumors (adenoma, carcinoma, and adenocarcinoma) were most frequently associated with lead exposure, and tumors of the brain, hematopoietic system, and lung were reported in some studies (IARC 1980, 1987). | ||||||||||
| 7440-38-2 | Arsenic and Inorganic Arsenic | 968 | Known – humans skin, lung, digestive tract, liver, urinary bladder, kidney, and lymphatic and hematopoietic systems | Group 1 | Not evaluated | NTP Research Studies | + | + | + | + |
| Lung, urinary bladder, skin | Enhances carcinogenicity of known carcinogens | Enhances carcinogenicity of known carcinogens | Liver, Adrenal, Lung | Liver, Adrenal, Lung, Ovary | ||||||
| 71-43-2 | Benzene | 846 | Known – humans (leukemia) | Group 1 | Negative | TR-289 | + | + | + | + |
| Animals – multiple organs | Leukemia, Lymphoma | Oral Cavity, Skin, Zymbal’s Gland | Oral Cavity, Zymbal’s Gland | Harderian Gland, Hematopoietic System, Lung, Preputial Gland, Zymbal’s Gland | Hematopoietic System, Lung, Mammary Gland, Ovary Zymbal’s Gland | |||||
| 79-01-6 | Trichloroethene (Trichloroethylene) | 842 | Known – humans, kidney | Group 1 | Negative | TR-002 | – | – | + | + |
| Animals – kidney and other organs | Kidney | Liver | Liver | |||||||
| Trichloroethene | Not evaluated | TR 243 | + | – | + | + | ||||
| Kidney, tubular cell | Liver | Liver | ||||||||
| Trichloroethene | Not evaluated | TR 273 (inadequate study) | Not evaluated | Not evaluated | Not evaluated | Not evaluated | ||||
| 7789-12-0 | Chromium compounds | 838 | Known – human (lung) | Group 1 | Positive | TR 546 (chromium VI) | + | + | + | + |
| Chromium VI | 128 | Animals (lung) (chromium VI) | Lung (chromium VI) 18540-29-9 | Oral cavity – squamous cell neoplasms | Oral cavity – squamous cell neoplasms | Small intestine neoplasms | Small intestine neoplasms | |||
| 127-18-4 | Tetrachloroethene (Tetrachloroethylene) | 753 | Reasonably anticipated | Group 2A | Negative | TR-013 | Inadequate | Inadequate | + | + |
| Animals – sufficient evidence (multiple organs) | Urinary Bladder | Liver | Liver | |||||||
| Tetrachloroethene (Tetrachloroethylene) | Negative | TR 311 | + | + | + | + | ||||
| Mononuclear cell leukemia, Renal tubular cell neoplasms | Mononuclear cell leukemia | Liver | Liver | |||||||
| 95-80-7 | 2,4-Diaminotoluene | 740 (other forms of toluene) | Reasonably anticipated | Group 2B | Positive | TR 162 | + | + | – | + |
| Animals sufficient evidence (multiple organs) | Liver | Liver, Mammary gland | Liver | |||||||
| 26471-62-5 | Toluene Diisocyanates | 740 | Reasonably anticipated | Group 3 | Positive | TR 251 | + | + | – | + |
| Animals sufficient evidence (multiple organs) | Subcutaneous fibromas and fibrosarcomas (combined) pancreatic acinar cell adenomas | Subcutaneous fibromas and fibrosarcomas (combined) pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland fibroadenomas | Hemangiomas or hemangiosarcomas (combined) as well as hepatocellular adenomas. | |||||||
| 7440-43-9 | Cadmium and Cadmium Compounds | 738 | Known – human (lung) | Group 1 | Not evaluated | Not tested by NTP in cancer studies | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| Sufficient – animals (lung & other organs) | Lung | |||||||||
| 7440-66-6 | Zinc (Dietary Zinc) | 710 | Not evaluated | Not evaluated | Not evaluated | TR 592 | –/+ | – | – | – |
| 7439-96-5 | Manganese | 687 | Not evaluated | Not evaluated | Not evaluated | Not tested in NTP cancer studies | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| 10034-96-5 | Manganese(II) Sulfate Monohydrate | Not evaluated | Not evaluated | TR 428 | – | – | –/+ | –/+ | ||
| 7440-50-8 | Copper | 666 | Not evaluated | Not evaluated | Not evaluated | Not tested in NTP cancer studies | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| 7440-02-0 | Nickel and Nickel Compounds | 664 | Known | Lung, Nasal Cavity | Not evaluated | |||||
| Lung | ||||||||||
| 10101-97-0 | Nickel Sulfate Hexahydrate | Evaluated in nickel group | Negative | TR-454 | – | – | – | – | ||
| 12035-72- | Nickel Subsulfide | Evaluated in nickel group | Negative | TR-453 | + | + | – | – | ||
| Lung, Adrenal medulla | Lung, Adrenal medulla | |||||||||
| 1313-99-1) | Nickel Oxide | Evaluated in nickel group | Negative | TR-451 | + | + | – | –/+ | ||
| Lung, Adrenal medulla | Lung, Adrenal medulla | |||||||||
| 75-01-4 | Vinyl Chloride | 616 | Known | Group 1 | Not evaluated | NTP Research Study | Not evaluated | Hemangiosarcomas, hepatocellular carcinomas, and mammary gland carcinomas | ND | Hemangiosarcomas and mammary gland carcinomas, lung |
| Liver | Liver and bile duct | |||||||||
| 1330-20-7 | Xylene | 599 | Not evaluated | Group 3 | Negative | TR-327 | – | – | – | – |
| 7439-97-6 | Mercury | 592 | Not evaluated | Group 3 | Not evaluated | Not tested in NTP cancer studies | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| 100-41-4 | Ethylbenzene | 576 | Not evaluated | Group 2B | Negative | TR-466 | + | + | ||
| Kidney, Tubular Cell, Testes | Kidney, Tubular Cell | |||||||||
| 117-81-7 | Bis(2-ethylhexyl) Phthalate | 575 | Reasonably anticipated | Group 2B | Negative | TR-601 | Not evaluated | + | + | + |
| (Di(2-ethylhexyl) Phthalate) | Liver | Liver | Liver | |||||||
| 7440-39-3 | Barium | 571 | Not evaluated | Not evaluated | Not evaluated | Not tested in NTP cancer studies | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| 75-09-2 | Methylene Chloride (Dichloromethane) | 555 | Reasonably anticipate (insufficient evidence in humans) | Group 2A | Positive | TR-306 | + | + | + | + |
| Mammary Gland | Mammary Gland | Lung, Liver | Lung, Liver | |||||||
| 75-35-4 | Vinylidene Chloride (1,1-Dichloroethene) | 539 | Reasonably anticipated | Group 2B | Negative | TR-582 | + | + | + | + |
| Kidney, Nasal Cavity, Malignant mesothelioma | Thyroid Gland Cell | Kidney | Hemangioma/Hemangioma sarcoma, Liver | |||||||
| Mononuclear cell leukemia | ||||||||||
| 67-66-3 | Chloroform | 538 | Reasonably anticipated | Group 2B | Negative | TR-000 (67-66-3) | + | – | + | – |
| Kidney, Tubular Cell | (uncertain findings) | Liver | Liver | |||||||
| 71-55-6 | 1,1,1-Trichloroethane | 528 | Reasonably Anticipated | Group 3 | Negative | TR-003 | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| 50-32-8 | 3,4-Benzo-pyrene | 521 | Included in Polyaromatic class as Reasonably anticipated based on animal data | Group 1 | Positive | Not tested in NTP cancer studies | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| 7439-89-6 | Iron | 506 | Not evaluated | Not evaluated | Not evaluated | Not tested in NTP cancer studies | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| 7440-36-0 | Antimony | 505 | Reasonably anticipated | Group 2B | Negative | TR - 590 | + | + | + | + |
| Antimony Trioxide Form Examined by NTP 1309-64-4 | Lung, Adrenal | Lung, Adrenal | Lung, Skin | Lung, Skin, Lymphoma | ||||||
| 107-06-2 | 1,2-Dichloroethane | 483 | Reasonably anticipated | Group 2B | Positive | TR-055 | + | + | Lung | + |
| Forestomach, Subcutaneous Tissue, Vascular System | Mammary Gland | Lung, Mammary Gland, Uterus, cervix | ||||||||
| 7440-79-00 | Beryllium | 475 | Known – lung cancer | Group 1 | Negative | Not tested in NTP cancer studies | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| 91-20-3 | Naphthalene | 473 | Reasonably anticipated | Not evaluated | Negative | TR-500 | + | + | Not evaluated | Evaluated |
| Nasal cavity | Nasal cavity | |||||||||
| 75-34-3 | 1,1-Dichloroethane | 468 | Reasonably anticipated | Not evaluated | Negative | TR-55 | + | + | + | + |
| Forestomach, hemangiosarcomas, skin | Mammary gland | Lung | Mammary gland uterus | |||||||
| 67-64-3 | Acetone | 452 | Not evaluated | Not evaluated | Not evaluated | Not evaluated | Not evaluated | Not evaluated | Not evaluated | Not evaluated |
U.S. Environmental Superfund information – total number of 1582 U.S. Superfund Sites included in this analysis.
National Toxicology Program (NTP) Report on Carcinogens (RoC); RoC classifications: Known – known to be a human carcinogen; Reasonably anticipated – reasonably anticipated to be a human carcinogen.
International Agency for Research on Cancer (IARC); IARC classification groups: Group 1 – Carcinogenic to humans; Group 2A – probably carcinogenic to humans; Group 2B – possibly carcinogenic to humans; Group 3 – nonclassifiable.
NTP Genetic Toxicology Salmonella results.
NTP cancer study results: +, some or clear evidence of cancer; +/–, equivocal evidence of cancer; −, no evidence of cancer; NE, not evaluated.
1.
Most frequently found organic compounds at 1582 U.S. Superfund sites.
2.
Most frequently found metals at 1582 U.S. Superfund sites.
Of the 30 most frequently found compounds or metals, 8 were reported as known human carcinogens, 13 as reasonably anticipated to be human carcinogens, and 9 as not being evaluated by the NTP RoC (Table ).
Of the 30 most frequently found compound or metal groups at U.S. Superfund sites, 8 were classified as known human carcinogens by the NTP RoC including: arsenic, benzene, trichloroethenes, chromium, beryllium, cadmium, nickels, and vinyl chloride.
Of the top 30 most frequently found groups of compounds or metals at U.S. Superfund sites, 13 were classified as reasonably anticipated to be human carcinogens by the NTP RoC including: lead, tetrachloroethene, toluene-based compounds, phthalate compounds, methylene chloride, vinylidene chloride, chloroform, 1,1,1-trichloroethane, benzopyrene, antimony, 1,2-dichloroethane, naphthalene, and dichloroethane.
Nine of the 30 most frequently found compounds or metals at the U.S. Superfund sites have not been evaluated by the NTP RoC including: zinc, manganese, copper, xylene, mercury, ethylbenzene, barium, iron, and acetone. Of these 9 compounds/metals not evaluated by the NTP RoC, one (ethylbenzene) has been evaluated by IARC and classified as group 2B (possibly carcinogenic to humans) (Figure ).
3.
IARC classification of most frequently found compounds and chemicals at U.S. Superfund sites. IARC Group 1 = The agent is carcinogenic to humans; IARC Group 2A = The agent is probably carcinogenic to humans; IARC Group 2B = The agent is possibly carcinogenic to humans; and IARC Group 3 = The agent is not evaluated or classifiable as to its carcinogenicity to humans.
Cancer potential of compound and metal mixtures is based on the NTP RoC data. A total of 921 mixtures of three compounds/metals were identified at the 1582 U.S. Superfund sites (Supplement Two). The cancer potentials of the most frequently found compound/metal mixtures at U.S. Superfund sites are summarized based on evaluations from the NTP RoC (Table ).
2. Mixtures of Three Compound/Metals with Two or Three Known Human Carcinogens Frequently Found at U.S. Superfund Sites.
| No. of Superfund Sites | Mixtures of Three Compound/Metals |
|---|---|
| Mixtures of Three with Three Known Compound/Metal Human Carcinogens | |
| 496 | Nickel compounds, Cadmium, Arsenic compounds |
| 451 | Benzene, Arsenic compounds, Trichloroethene |
| 433 | Benzene, Cadmium, Arsenic compounds |
| 424 | Nickel compounds, Benzene, Arsenic compounds |
| 420 | Benzene, Vinyl Chloride, Trichloroethene |
| 414 | Cadmium, Arsenic compounds, Trichloroethene |
| 391 | Nickel compounds, Arsenic compounds, Trichloroethene |
| 389 | Nickel compounds, Benzene, Cadmium |
| 386 | Vinyl Chloride, Arsenic compounds, Trichloroethene |
| 385 | Beryllium, Cadmium, Arsenic compounds |
| 379 | Nickel compounds, Beryllium, Arsenic compounds |
| 379 | Benzene, Cadmium, Trichloroethene |
| 368 | Benzene, Vinyl Chloride, Arsenic compounds |
| 366 | Nickel compounds, Beryllium, Cadmium |
| 366 | Nickel compounds, Cadmium, Trichloroethene |
| 360 | Nickel compounds, Benzene, Trichloroethene |
| 328 | Benzene, Beryllium, Arsenic compounds |
| 321 | Cadmium, Vinyl Chloride, Arsenic compounds |
| Mixtures of Three with Two Known Compound/Metal Human Carcinogens | |
| 611 | Lead, Cadmium, Arsenic compounds |
| 549 | Nickel compounds, Lead, Arsenic compounds |
| 518 | Benzene, Lead, Arsenic compounds |
| 517 | Nickel compound, Lead, Cadmium |
| 500 | Tetrachloroethene, Benzene, Trichloroethene |
| 478 | Lead, Arsenic compounds, Trichloroethene |
| 474 | Tetrachloroethene, Arsenic compounds, Trichloroethene |
| 461 | Tetrachloroethene, Vinyl Chloride, Trichloroethene |
| 455 | Benzene, Lead, Cadmium |
| 452 | Benzene, Lead, Trichloroethene |
| 433 | Nickel compound, Benzene, Lead |
| 433 | Lead, Cadmium, Trichloroethene |
There were 18 compound/metal mixtures for which all three mixture components are listed in the NTP RoC as known human carcinogens (Figure ; Supplement Two).
4.
Most frequent mixtures of three known human carcinogens at U.S. Superfund sites.
There were 192 mixtures in which two of the three compound/metal components are listed in the NTP RoC as known human carcinogens (Supplement Two). The 18 mixtures with all components being human carcinogens by the NTP RoC and the 12 most frequent mixtures with two of the components being known human carcinogens are given in Table . The cancer target organ, as determined from experimental studies, varied depending on the compound/metal (Table ), and cancer or disease could be caused at a variety of target sites including liver, lung, kidney, mammary gland, and other organs.
3. Cancer Target Organs for Frequent U.S. Superfund Compound/Metal Mixtures.
| Mixture of Three | No. of Superfund Sites | Human Cancer Target Organ |
|---|---|---|
| Nickel, Cadmium, Arsenic | 496 | Nickel (lung) |
| Cadmium (lung) | ||
| Arsenic (skin, lung, digestive tract, liver, urinary bladder, kidney, and lymphatic and hematopoietic systems) | ||
| Benzene, Arsenic, Trichloroethene | 451 | Benzene (lymphoma, leukemia) |
| Arsenic (skin, lung, digestive tract, liver, urinary bladder, kidney, and lymphatic and hematopoietic systems) | ||
| Trichloroethene (kidney) | ||
| Benzene, Cadmium, Arsenic | 433 | Benzene (lymphoma, leukemia) |
| Cadmium (lung) | ||
| Arsenic (skin, lung, digestive tract, liver, urinary bladder, kidney, and lymphatic and hematopoietic systems) | ||
| Benzene, Vinyl Chloride, Trichloroethene | 420 | Benzene (lymphoma, leukemia) |
| Vinyl chloride (liver and bile duct) | ||
| Trichloroethene (kidney) | ||
| Arsenic, Vinyl Chloride, Trichloroethene | 386 | Arsenic (skin, lung, digestive tract, liver, urinary bladder, kidney, and lymphatic and hematopoietic systems) |
| Vinyl chloride (liver and bile duct) | ||
| Trichloroethylene (kidney) |
Some of the commonly found mixtures at U.S. Superfund sites were nickel, arsenic, and cadmium (496 sites); benzene, arsenic, trichloroethene (451 sites); benzene, vinyl chloride, trichloroethene (420 sites); and arsenic, vinyl chloride, trichloroethene (386 sites). Compounds and metals associated with the development of liver cancer at the U.S. Superfund sites included vinyl chloride and arsenic. Those associated with the development of lung cancer included many of the metals, such as cadmium, nickel, arsenic, and beryllium. Benzene is associated with the development of lymphoma/leukemia. Thus, mixture exposure could cause cancer at multiple target sites.
Discussion and Conclusions
Cancer hazards of compounds, metals, and compound/metal mixtures frequently found at U.S. Superfund sites were summarized and correlated with their potential to cause cancer based on results of NTP rodent cancer studies, the RoC monographs, and data from IARC. The individual components of a mixture may have different organ target sites of cancer or activate different cancer pathways (e.g., genotoxic pathways, nongenotoxic pathways, oxidative damage, etc.). Many of the compounds and metals found at U.S. Superfund sites have been reported to cause cancer at some of the most frequent sites for cancer in humans including the lung, liver, colon and rectum, urinary bladder, reproductive organs, or the lymphatic system. , Thus, mixture exposure has the potential to cause cancer at multiple target organ sites.
The carcinogenic properties or preferential site of cancer induction by organic compounds is varied and is often dependent on the route, duration, and amount of exposure, metabolic processes, genotoxic or epigenetic factors, hormonal disruption, population susceptibility, and other biological parameters such as the target cell, DNA repair mechanisms, and tissue/tumor microenvironment. The existence of compounds or metals may be complex in themselves within our 3-mixture paradigm, and although these compounds or metals may be commonly found together at U.S. Superfund sites, this does not automatically imply equal coexposures; many other factors as outlined above must be factored into the exposures and cancer outcomes.
For example, halogenated chemicals are common chemicals found at U.S. Superfund sites, and many of these halogenated chemicals (e.g., trichloroethene, tetrachloroethene, and vinyl chloride) are reported by IARC to cause liver cancer. However, other halogenated chemicals may cause cancer at other target organ sites (e.g. trichloroethene is associated with kidney cancers). There are different forms of metals at U.S. Superfund sites, and not all metal forms may have enough information for an IARC evaluation of their carcinogenic potential. For example, chromium VI is classified in IARC group 1 (carcinogenic to humans), while there is not enough information for an IARC classification of metallic chromium. Other metals at U.S. Superfund sites also have not been evaluated by IARC for carcinogenic potential (e.g., copper, xylene, mercury, barium, iron) because of a lack of sufficient toxicity studies.
In general, the toxicity of mixtures has not been well studied especially the effects of long-term mixture exposures and cancer, and IARC generally reviews carcinogenic potential one compound at a time. It is recommended that, in order to adequately evaluate the effects of chemical mixtures, an integrated, systematic, and collaborative approach is needed across different disciplines, such as toxicology, epidemiology, exposure science, risk assessment, and statistics to make proper and accurate assessments of mixture exposures and outcomes. It is evident that humans experience complex exposures throughout their lifetime, and many of the current approaches for understanding the mechanisms of chemically induced carcinogenesis have not taken this into account. There are many challenges in designing experimental research studies to evaluate the effects of mixtures and understanding the possible outcomes to inform hazard or risk assessments; however, new concepts and approaches consisting of chemical screening, transgenic model-based, and disease-centered methods have been proposed for evaluating mixtures and cancer development.
In this summary, some of the most frequent organic compounds found at Superfund sites that are classified as known human carcinogens include benzene, benzo[a]pyrene, bis(2-ethylhexyl) phthalate, chloroform, 1,1-dichloroethene, 1,2-dichloroethane, ethylbenzene, methylene chloride, 1,1,1-trichloroethane, tetrachloroethene, trichloroethene, and vinyl chloride. The most frequent metals identified at Superfund sites are classified as known or reasonably anticipated to be human carcinogens and included arsenic, beryllium, cadmium, nickel, and lead.
Ten “key characteristics” are used to describe different mechanisms of carcinogenicity, and any one compound or metal may have several “key characteristics”. For example, benzene is thought to cause carcinogenic activity by a variety of mechanisms including immunosuppression, DNA mutations, metabolic alterations, and/or oxidative damage. Metals may cause oxidative damage leading to cancer. Compound and metal exposures acting by different cancer mechanisms may work together to exert a greater toxic and carcinogenic effect than exposure to one compound alone.
Cancer hazard evaluations have not been performed on compound/metal mixtures found at U.S. Superfund sites. The location of many of the U.S. Superfund sites are in regions in the U.S. where a continuing rise in temperature occurs and other social factors are present that may make populations particularly sensitive to cancer development. ,
Toxicology and cancer studies of mixtures found at U.S. Superfund sites would provide needed information for cancer hazard evaluation. Such information could be used to develop strategies to protect the public, particularly segments of the population that live near U.S. Superfund sites. Mixture toxicology studies could include both in vivo and in vitro studies to provide data for identification of early cancer disease biomarkers of exposure. Use of these early cancer biomarkers would help in detecting cancer in vulnerable populations living near U.S. Superfund sites.
Supplementary Material
Acknowledgments
We thank Dr. Kembra Howdeshell and Dr. Kristine Witt, NIEHS, for their review of the manuscript.
Biographies
June K. Dunnick received a B.S. degree from Cornell University, Ithaca, New York, a Ph.D. from Weill Cornell Graduate School of Medical Sciences, New York, New York, and an MBA from Kenan-Flagler Business School, University of North Carolina at Chapel Hill, North Carolina. She completed postdoctoral work in the Department of Biochemistry, University of Rochester Medical School, Rochester, New York. She is currently a senior scientist and toxicologist at the National Institute of Environmental Health Sciences and conducts research in environmental health sciences.
Charles P. Schmitt received a B.S. degree in physics and a Ph.D. in computer science, both from the University of North Carolina at Chapel Hill. His early career was in industry working for several companies focusing on software engineering, data analysis, and data mining before joining BD Technologies where his work shifted to developing biomedical data management and analysis platforms to support stem cell research. Dr. Schmitt later joined the Renaissance Computing Institute (RENCI), followed by employment at the National Institute of Environmental Health Sciences where he is currently a Senior Scientist and Director of the Office of Data Science.
Darlene Dixon received a B.S. degree from Tuskegee University, a D.V.M. from the College of Veterinary Medicine, Tuskegee University, Tuskegee, Alabama, and a Ph.D. from Michigan State University, East Lansing, Michigan. She completed postdoctoral training at the Laboratory Animal Research Center at The Rockefeller University, New York, New York. She is a Diplomate in the American College of Veterinary Pathologists and is currently an Acting Branch Chief and Senior Investigator in the Division of Translational Toxicology at the National Institute of Environmental Health Sciences.
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.chemrestox.4c00506.
All authors conducted the conceptualization, methodology, formal analysis, investigation, and writing of the manuscript.
The NIEHS intramural program supported this work (ZIA ES103349-01; ZIA ES021196-27; ZIA ES103364-02).
The authors declare no competing financial interest.
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