The National Toxicology Program strives to raise awareness of cancer hazards in our environment. ... more The National Toxicology Program strives to raise awareness of cancer hazards in our environment. Identifying cancer hazards is key to primary prevention, informing public health decision making, and decreasing the global cancer burden. In December 2021, the US congressionally mandated 15th Report on Carcinogens was released, adding 8 new substances to the cumulative report. Chronic infection with Helicobacter pylori is listed as “known to be a human carcinogen.” Antimony trioxide and 6 haloacetic acids found as water disinfection by-products—dichloroacetic acid, dibromoacetic acid, bromochloroacetic acid, tribromoacetic acid, bromodichloroacetic acid, chlorodibromoacetic acid—are listed as “reasonably anticipated to be a human carcinogen.” A new dashboard provides interactive visualization and interrogation of the 256 listed substances, their uses, and associated cancers. Also, the National Toxicology Program recently published a Cancer Hazard Assessment Report on exposure scenarios...
Systematic review methods aim to increase transparency, rigor, and reproducibility of literature-... more Systematic review methods aim to increase transparency, rigor, and reproducibility of literature-based evaluations, for the purposes of reaching a weight-of-evidence conclusion. These methods are b...
BACKGROUND: Increasingly, risk of bias tools are used to evaluate epidemiologic studies as part o... more BACKGROUND: Increasingly, risk of bias tools are used to evaluate epidemiologic studies as part of evidence synthesis (evidence integration), often involving meta-analyses. Some of these tools consider hypothetical randomized controlled trials (RCTs) as gold standards. METHODS: We review the strengths and limitations of risk of bias assessments, in particular, for reviews of observational studies of environmental exposures, and we also comment more generally on methods of evidence synthesis. RESULTS: Although RCTs may provide a useful starting point to think about bias, they do not provide a gold standard for environmental studies. Observational studies should not be considered inherently biased vs. a hypothetical RCT. Rather than a checklist approach when evaluating individual studies using risk of bias tools, we call for identifying and quantifying possible biases, their direction, and their impacts on parameter estimates. As is recognized in many guidelines, evidence synthesis requires a broader approach than simply evaluating risk of bias in individual studies followed by synthesis of studies judged unbiased, or with studies given more weight if judged less biased. It should include the use of classical considerations for judging causality in human studies, as well as triangulation and integration of animal and mechanistic data. CONCLUSIONS: Bias assessments are important in evidence synthesis, but we argue they can and should be improved to address the concerns we raise here. Simplistic, mechanical approaches to risk of bias assessments, which may particularly occur when these tools are used by nonexperts, can result in erroneous conclusions and sometimes may be used to dismiss important evidence. Evidence synthesis requires a broad approach that goes beyond assessing bias in individual human studies and then including a narrow range of human studies judged to be unbiased in evidence synthesis.
Cancer Epidemiology, Biomarkers & Prevention, 2019
Background: Red and processed meats have been implicated as risk factors in the development of co... more Background: Red and processed meats have been implicated as risk factors in the development of colorectal cancer in U.S. women, but associations with cooking practices are less well established. Methods: Data are from the Sister Study, a cohort of women ages 35 to 74 years from the United States and Puerto Rico who have a sister diagnosed with breast cancer. Red and processed meat consumption, meat cooking practices, and intake of common meat products were collected at baseline using self-administered questionnaires (N = 48,704). Multivariable HRs (HRadj) and 95% confidence intervals (95% CI) were estimated. Results: During a median 8.7 years' follow-up (range <1–12.7 years), 216 colorectal cancer cases were diagnosed. In categorical analyses, an increased risk of colorectal cancer was seen in the highest quartile of processed meat consumption compared with the lowest [HRadj = 1.52 (95% CI, 1.01–2.30); Ptrend = 0.02], and for specific meat products, including breakfast sausag...
JNCI: Journal of the National Cancer Institute, 2019
The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous ... more The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert advisory group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs program. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating, and integrating evidence to identify causes of human cancer. The advancements adopted include the strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on...
This commentary is written in response to a recent commentary in Carcinogenesis that provides sev... more This commentary is written in response to a recent commentary in Carcinogenesis that provides several viewpoints on the International Agency for Research on Cancer’s (IARC) Monographs program on cancer hazard identification. This commentary offers an alternative viewpoint of the role of cancer hazard identification derived from cancer epidemiology studies in risk characterization, as well as clarification on the previous commentary’s interpretation of the purpose of the Monographs and other programs of cancer hazard identification and how IARC communicates the findings of the Monographs. Open in a separate windowGraphical Abstract
Epigenetic changes in gene expression due to extensive CpG island methylation is now accepted as ... more Epigenetic changes in gene expression due to extensive CpG island methylation is now accepted as the main cause of inactivation of the p16 gene. More recently, it has been suggested that the human ras association domain family (RASSF) 1 gene, cloned from the lung tumor-suppressor locus 3p21.3, also may be inactivated by methylation. It consists of two major alternative transcripts, RASSF1A and RASSF1C. Epigenetic inactivation of isoform A was observed in several carcinomas and tumor cell lines. In this study, promoter hypermethylation of RASSF1A and p16 was investigated in 83 hepatocellular carcinoma (HCC) tissue samples from Taiwan and in two HCC cell lines (Hep3B and HepG2). High frequencies (85% and 47%, respectively) of methylation of the CpG island promoters of RASSF1A and p16 were found in the HCC tissues. The methylation of RASSF1A also was detected in Hep3B cells but not in HepG2 cells; p16 was not methylated in either cell line. Methylation status was determined in 12 normal control liver tissues and 10 adjacent nontumor tissues. No methylation was found in normal liver control tissues for both RASSF1A and p16; methylation was detected in one of 10 and seven of 10 adjacent nontumor tissue sampless for p16 and RASSF1A, respectively, in subjects with positive tumors. These data indicate that aberrant methylation of the CpG island promoters of both genes is a frequent occurrence in hepatocarcinogenesis. The high frequency of RASSF1A methylation in adjacent tissues suggests that this may be an early event. The relationship between methylation status and clinical parameters and tumor markers, including DNA damage resulting from aflatoxin B(1) (AFB(1)), an environmental carcinogen, and p53 status, also was analyzed. A statistically significant association was found between RASSF1A methylation status and the level of AFB(1)-DNA adducts in tumor tissues. No association was found between methylation status and p53 status. These results suggest the hypothesis that exposure to environmental carcinogens may be involved in altered methylation of genes involved in cancer development.
Forty-five years after the World Health Organization recognized cancer as a world health problem ... more Forty-five years after the World Health Organization recognized cancer as a world health problem by creating the International Agency for Research on Cancer (IARC), carcino genic exposures in the workplace remain a concern. Many known and suspected carcinogens are found in today's workplaces, and uncertainties about the health effects of exposure to these hazards have delayed regulatory action and the search for safer alternatives. In this review we focus primarily on chemicals, metals, dusts, and physical agents for which there is widespread human exposure, predominantly in occupational settings, and we address unresolved questions regarding carcino genicity. Most of these agents are in IARC Groups 2A and 2B-agents for which there is sufficient evidence of carcinogenicity in animals but limited evidence for carcinogenicity in humans.
Journal of Exposure Science & Environmental Epidemiology, 2020
Systematic reviews are powerful tools for drawing causal inference for evidence-based decisionmak... more Systematic reviews are powerful tools for drawing causal inference for evidence-based decisionmaking. Published systematic reviews and meta-analyses of environmental and occupational epidemiology studies have increased dramatically in recent years; however, the quality and utility of published reviews are variable. Most methodologies were adapted from clinical epidemiology and have not been adequately modified to evaluate and integrate evidence from observational epidemiology studies assessing environmental and occupational hazards, especially in evaluating the quality of exposure assessments. Although many reviews conduct a systematic and transparent assessment for the potential for bias, they are often deficient in subsequently integrating across a body of evidence. A cohesive review considers the impact of the direction and magnitude of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
International Journal of Environmental Research and Public Health
Harmonized language is critical for helping researchers to find data, collecting scientific data ... more Harmonized language is critical for helping researchers to find data, collecting scientific data to facilitate comparison, and performing pooled and meta-analyses. Using standard terms to link data to knowledge systems facilitates knowledge-driven analysis, allows for the use of biomedical knowledge bases for scientific interpretation and hypothesis generation, and increasingly supports artificial intelligence (AI) and machine learning. Due to the breadth of environmental health sciences (EHS) research and the continuous evolution in scientific methods, the gaps in standard terminologies, vocabularies, ontologies, and related tools hamper the capabilities to address large-scale, complex EHS research questions that require the integration of disparate data and knowledge sources. The results of prior workshops to advance a harmonized environmental health language demonstrate that future efforts should be sustained and grounded in scientific need. We describe a community initiative who...
Over 10 million U.S. adults and ∼15%–20% worldwide work night shifts. Shift work, a complex expos... more Over 10 million U.S. adults and ∼15%–20% worldwide work night shifts. Shift work, a complex exposure scenario, can cause circadian disruption (CD) and possible adverse health effects such as breast cancer. Although there have been a plethora of meta-analysis on shift work and breast cancer, these are not very informative because of inconsistent definition of shift work across studies.The U.S. National Toxicology Program (NTP) conducted a systematic review (SR) to determine whether night shift work should be listed in the Report on Carcinogens (RoC). The SR included a review of cancer epidemiology studies and mechanistic studies of CD and cancer. NTP developed a protocol, based on scientific input gathered during a public workshop, which identified key issues for conducting the SR: definition of surrogates of night work related to CD, inclusion of multiple metrics of night work, information on early age at exposure when breast tissue is most susceptible, cancer subtypes, effect modif...
Human erythroleukemic K562 cells are known to have several erythroid properties. K562 cells posse... more Human erythroleukemic K562 cells are known to have several erythroid properties. K562 cells possess Rh mRNAs, but expression of Rh proteins has not previously been reported. We immunoprecipitated Rh protein from K562 cell lysate using rabbit anti-Rh and detected Rh(D) antigens on K562 cells using fluorescence-activated cell sorting (FACS). These results suggest that K562 cells will be useful as an expression model for most Rh antigens. We also cloned a new Rh(D) cDNA isoform (RhK562- II), from a K562 cDNA library using polymerase chain reaction (PCR) with 5′ and 3′ end oligonucleotides of the published Rh(e/E) antigen encoding cDNA sequence as primers. Sequence analysis showed that RhK562- II is composed of 951 nucleotides (316 amino acids), identical to the first 939 nucleotides (exons 1 to 6) of one of the Rh(D) cDNAs (RhXIII), except for nucleotide 654 (C-->XG exchange). However, this exchange is the same as that of another published Rh(D) cDNA (RhPII cDNA). RhK562-II is depri...
Objective and systematic methods to search, review, and synthesize published studies are a fundam... more Objective and systematic methods to search, review, and synthesize published studies are a fundamental aspect of carcinogen hazard classification. Systematic review is a historical strength of the International Agency for Research on Cancer (IARC) Monographs Program and the United States National Toxicology Program (NTP) Office of the Report on Carcinogens (RoC). Both organizations are tasked with evaluating peer-reviewed, published evidence to determine whether specific substances, exposure scenarios, or mixtures pose a cancer hazard to humans. This evidence synthesis is based on objective, transparent, published methods that call for extracting and interpreting data in a systematic manner from multiple domains, including a) human exposure, b) epidemiological evidence, c) evidence from experimental animals, and d) mechanistic evidence. The process involves multiple collaborators and requires an extensive literature search, review, and synthesis of the evidence. Several online tools have been implemented to facilitate these collaborative systematic review processes. Specifically, Health Assessment Workplace Collaborative (HAWC) and Table Builder are custom solutions designed to record and share the results of the systematic literature search, data extraction, and analyses. In addition, a content management system for web-based project management and document submission has been adopted to enable access to submitted drafts simultaneously by multiple co-authors and to facilitate their peer review and revision. These advancements in cancer hazard classification have applicability in multiple systematic review efforts.
The National Toxicology Program strives to raise awareness of cancer hazards in our environment. ... more The National Toxicology Program strives to raise awareness of cancer hazards in our environment. Identifying cancer hazards is key to primary prevention, informing public health decision making, and decreasing the global cancer burden. In December 2021, the US congressionally mandated 15th Report on Carcinogens was released, adding 8 new substances to the cumulative report. Chronic infection with Helicobacter pylori is listed as “known to be a human carcinogen.” Antimony trioxide and 6 haloacetic acids found as water disinfection by-products—dichloroacetic acid, dibromoacetic acid, bromochloroacetic acid, tribromoacetic acid, bromodichloroacetic acid, chlorodibromoacetic acid—are listed as “reasonably anticipated to be a human carcinogen.” A new dashboard provides interactive visualization and interrogation of the 256 listed substances, their uses, and associated cancers. Also, the National Toxicology Program recently published a Cancer Hazard Assessment Report on exposure scenarios...
Systematic review methods aim to increase transparency, rigor, and reproducibility of literature-... more Systematic review methods aim to increase transparency, rigor, and reproducibility of literature-based evaluations, for the purposes of reaching a weight-of-evidence conclusion. These methods are b...
BACKGROUND: Increasingly, risk of bias tools are used to evaluate epidemiologic studies as part o... more BACKGROUND: Increasingly, risk of bias tools are used to evaluate epidemiologic studies as part of evidence synthesis (evidence integration), often involving meta-analyses. Some of these tools consider hypothetical randomized controlled trials (RCTs) as gold standards. METHODS: We review the strengths and limitations of risk of bias assessments, in particular, for reviews of observational studies of environmental exposures, and we also comment more generally on methods of evidence synthesis. RESULTS: Although RCTs may provide a useful starting point to think about bias, they do not provide a gold standard for environmental studies. Observational studies should not be considered inherently biased vs. a hypothetical RCT. Rather than a checklist approach when evaluating individual studies using risk of bias tools, we call for identifying and quantifying possible biases, their direction, and their impacts on parameter estimates. As is recognized in many guidelines, evidence synthesis requires a broader approach than simply evaluating risk of bias in individual studies followed by synthesis of studies judged unbiased, or with studies given more weight if judged less biased. It should include the use of classical considerations for judging causality in human studies, as well as triangulation and integration of animal and mechanistic data. CONCLUSIONS: Bias assessments are important in evidence synthesis, but we argue they can and should be improved to address the concerns we raise here. Simplistic, mechanical approaches to risk of bias assessments, which may particularly occur when these tools are used by nonexperts, can result in erroneous conclusions and sometimes may be used to dismiss important evidence. Evidence synthesis requires a broad approach that goes beyond assessing bias in individual human studies and then including a narrow range of human studies judged to be unbiased in evidence synthesis.
Cancer Epidemiology, Biomarkers & Prevention, 2019
Background: Red and processed meats have been implicated as risk factors in the development of co... more Background: Red and processed meats have been implicated as risk factors in the development of colorectal cancer in U.S. women, but associations with cooking practices are less well established. Methods: Data are from the Sister Study, a cohort of women ages 35 to 74 years from the United States and Puerto Rico who have a sister diagnosed with breast cancer. Red and processed meat consumption, meat cooking practices, and intake of common meat products were collected at baseline using self-administered questionnaires (N = 48,704). Multivariable HRs (HRadj) and 95% confidence intervals (95% CI) were estimated. Results: During a median 8.7 years' follow-up (range <1–12.7 years), 216 colorectal cancer cases were diagnosed. In categorical analyses, an increased risk of colorectal cancer was seen in the highest quartile of processed meat consumption compared with the lowest [HRadj = 1.52 (95% CI, 1.01–2.30); Ptrend = 0.02], and for specific meat products, including breakfast sausag...
JNCI: Journal of the National Cancer Institute, 2019
The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous ... more The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert advisory group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs program. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating, and integrating evidence to identify causes of human cancer. The advancements adopted include the strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on...
This commentary is written in response to a recent commentary in Carcinogenesis that provides sev... more This commentary is written in response to a recent commentary in Carcinogenesis that provides several viewpoints on the International Agency for Research on Cancer’s (IARC) Monographs program on cancer hazard identification. This commentary offers an alternative viewpoint of the role of cancer hazard identification derived from cancer epidemiology studies in risk characterization, as well as clarification on the previous commentary’s interpretation of the purpose of the Monographs and other programs of cancer hazard identification and how IARC communicates the findings of the Monographs. Open in a separate windowGraphical Abstract
Epigenetic changes in gene expression due to extensive CpG island methylation is now accepted as ... more Epigenetic changes in gene expression due to extensive CpG island methylation is now accepted as the main cause of inactivation of the p16 gene. More recently, it has been suggested that the human ras association domain family (RASSF) 1 gene, cloned from the lung tumor-suppressor locus 3p21.3, also may be inactivated by methylation. It consists of two major alternative transcripts, RASSF1A and RASSF1C. Epigenetic inactivation of isoform A was observed in several carcinomas and tumor cell lines. In this study, promoter hypermethylation of RASSF1A and p16 was investigated in 83 hepatocellular carcinoma (HCC) tissue samples from Taiwan and in two HCC cell lines (Hep3B and HepG2). High frequencies (85% and 47%, respectively) of methylation of the CpG island promoters of RASSF1A and p16 were found in the HCC tissues. The methylation of RASSF1A also was detected in Hep3B cells but not in HepG2 cells; p16 was not methylated in either cell line. Methylation status was determined in 12 normal control liver tissues and 10 adjacent nontumor tissues. No methylation was found in normal liver control tissues for both RASSF1A and p16; methylation was detected in one of 10 and seven of 10 adjacent nontumor tissue sampless for p16 and RASSF1A, respectively, in subjects with positive tumors. These data indicate that aberrant methylation of the CpG island promoters of both genes is a frequent occurrence in hepatocarcinogenesis. The high frequency of RASSF1A methylation in adjacent tissues suggests that this may be an early event. The relationship between methylation status and clinical parameters and tumor markers, including DNA damage resulting from aflatoxin B(1) (AFB(1)), an environmental carcinogen, and p53 status, also was analyzed. A statistically significant association was found between RASSF1A methylation status and the level of AFB(1)-DNA adducts in tumor tissues. No association was found between methylation status and p53 status. These results suggest the hypothesis that exposure to environmental carcinogens may be involved in altered methylation of genes involved in cancer development.
Forty-five years after the World Health Organization recognized cancer as a world health problem ... more Forty-five years after the World Health Organization recognized cancer as a world health problem by creating the International Agency for Research on Cancer (IARC), carcino genic exposures in the workplace remain a concern. Many known and suspected carcinogens are found in today's workplaces, and uncertainties about the health effects of exposure to these hazards have delayed regulatory action and the search for safer alternatives. In this review we focus primarily on chemicals, metals, dusts, and physical agents for which there is widespread human exposure, predominantly in occupational settings, and we address unresolved questions regarding carcino genicity. Most of these agents are in IARC Groups 2A and 2B-agents for which there is sufficient evidence of carcinogenicity in animals but limited evidence for carcinogenicity in humans.
Journal of Exposure Science & Environmental Epidemiology, 2020
Systematic reviews are powerful tools for drawing causal inference for evidence-based decisionmak... more Systematic reviews are powerful tools for drawing causal inference for evidence-based decisionmaking. Published systematic reviews and meta-analyses of environmental and occupational epidemiology studies have increased dramatically in recent years; however, the quality and utility of published reviews are variable. Most methodologies were adapted from clinical epidemiology and have not been adequately modified to evaluate and integrate evidence from observational epidemiology studies assessing environmental and occupational hazards, especially in evaluating the quality of exposure assessments. Although many reviews conduct a systematic and transparent assessment for the potential for bias, they are often deficient in subsequently integrating across a body of evidence. A cohesive review considers the impact of the direction and magnitude of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
International Journal of Environmental Research and Public Health
Harmonized language is critical for helping researchers to find data, collecting scientific data ... more Harmonized language is critical for helping researchers to find data, collecting scientific data to facilitate comparison, and performing pooled and meta-analyses. Using standard terms to link data to knowledge systems facilitates knowledge-driven analysis, allows for the use of biomedical knowledge bases for scientific interpretation and hypothesis generation, and increasingly supports artificial intelligence (AI) and machine learning. Due to the breadth of environmental health sciences (EHS) research and the continuous evolution in scientific methods, the gaps in standard terminologies, vocabularies, ontologies, and related tools hamper the capabilities to address large-scale, complex EHS research questions that require the integration of disparate data and knowledge sources. The results of prior workshops to advance a harmonized environmental health language demonstrate that future efforts should be sustained and grounded in scientific need. We describe a community initiative who...
Over 10 million U.S. adults and ∼15%–20% worldwide work night shifts. Shift work, a complex expos... more Over 10 million U.S. adults and ∼15%–20% worldwide work night shifts. Shift work, a complex exposure scenario, can cause circadian disruption (CD) and possible adverse health effects such as breast cancer. Although there have been a plethora of meta-analysis on shift work and breast cancer, these are not very informative because of inconsistent definition of shift work across studies.The U.S. National Toxicology Program (NTP) conducted a systematic review (SR) to determine whether night shift work should be listed in the Report on Carcinogens (RoC). The SR included a review of cancer epidemiology studies and mechanistic studies of CD and cancer. NTP developed a protocol, based on scientific input gathered during a public workshop, which identified key issues for conducting the SR: definition of surrogates of night work related to CD, inclusion of multiple metrics of night work, information on early age at exposure when breast tissue is most susceptible, cancer subtypes, effect modif...
Human erythroleukemic K562 cells are known to have several erythroid properties. K562 cells posse... more Human erythroleukemic K562 cells are known to have several erythroid properties. K562 cells possess Rh mRNAs, but expression of Rh proteins has not previously been reported. We immunoprecipitated Rh protein from K562 cell lysate using rabbit anti-Rh and detected Rh(D) antigens on K562 cells using fluorescence-activated cell sorting (FACS). These results suggest that K562 cells will be useful as an expression model for most Rh antigens. We also cloned a new Rh(D) cDNA isoform (RhK562- II), from a K562 cDNA library using polymerase chain reaction (PCR) with 5′ and 3′ end oligonucleotides of the published Rh(e/E) antigen encoding cDNA sequence as primers. Sequence analysis showed that RhK562- II is composed of 951 nucleotides (316 amino acids), identical to the first 939 nucleotides (exons 1 to 6) of one of the Rh(D) cDNAs (RhXIII), except for nucleotide 654 (C-->XG exchange). However, this exchange is the same as that of another published Rh(D) cDNA (RhPII cDNA). RhK562-II is depri...
Objective and systematic methods to search, review, and synthesize published studies are a fundam... more Objective and systematic methods to search, review, and synthesize published studies are a fundamental aspect of carcinogen hazard classification. Systematic review is a historical strength of the International Agency for Research on Cancer (IARC) Monographs Program and the United States National Toxicology Program (NTP) Office of the Report on Carcinogens (RoC). Both organizations are tasked with evaluating peer-reviewed, published evidence to determine whether specific substances, exposure scenarios, or mixtures pose a cancer hazard to humans. This evidence synthesis is based on objective, transparent, published methods that call for extracting and interpreting data in a systematic manner from multiple domains, including a) human exposure, b) epidemiological evidence, c) evidence from experimental animals, and d) mechanistic evidence. The process involves multiple collaborators and requires an extensive literature search, review, and synthesis of the evidence. Several online tools have been implemented to facilitate these collaborative systematic review processes. Specifically, Health Assessment Workplace Collaborative (HAWC) and Table Builder are custom solutions designed to record and share the results of the systematic literature search, data extraction, and analyses. In addition, a content management system for web-based project management and document submission has been adopted to enable access to submitted drafts simultaneously by multiple co-authors and to facilitate their peer review and revision. These advancements in cancer hazard classification have applicability in multiple systematic review efforts.
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