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NTP — Nickel: HHS Response to RFC, October 24, 2003

October 24, 2003

Mr. Neil J. King 
Wilmer, Cutler & Pickering 
2445 M. Street, N.W. 
Washington, D.C. 20037-1420

Dear Mr. King:

I am writing in response to your April 9 request for correction filed under the National Institutes of Health (NIH) "Guidelines for Ensuring the Quality of Information Disseminated to the Public" (NIH Guidelines).1 You asked that the summary profiles for nickel com~ounds and metallic nickel contained in the Tenth Edition of the Report on Carcinogens (10 RoC) be revised based on concerns expressed in your letter. Many of the concerns outlined in your letter suggest an incomplete understanding of the review process used by the National Toxicology Program in evaluating metallic nickel and nickel compounds for listing in the 10th RoC. To insure clarity, I will respond to your concerns after first summarizing the review process used for nickel compounds and metallic nickel.

Nickel compounds, metallic nickel and nickel alloys were nominated for listing in the RoC and reviewed by the formal, multi-step process used for all RoC nominations. Once an agent has been chosen for review, the process begins with the preparation of a background document that summarizes the relevant scientific information relating to human exposure to and the carcinogenic potential of the nominated agent. The background document is intended to be concise, comprehensive and unbiased providing summaries on all relevant studies, both positive and negative, that can be found in the peer-reviewed scientific literature. The background document provides the bulk of the information that serves as the basis of the recommendations of the review committees and ultimately the listing in the RoC. The full background document for Metallic Nickel and Nickel Alloys is available on the web at I O/Ni.pdf, and the background document for Nickel Compounds is available in hard copy or on CD and can be obtained from: Dr. C.W. Jameson, Report on Carcinogens, NIEHS, MD EC-14, 79 T.W. Alexander Drive, Building 4401, Room 3118, P.O. Box 12233, Research Triangle Park, NC 27709 (919/541-4096; FAX 919/541-2242; email

The formal review of an agent for possible listing in the RoC includes evaluation by two Federal scientific review groups and one non-governmental scientific peer-review body (a subcommittee of the NTP Board of Scientific Counselors). Each group reviews the relevant data on the carcinogenicity and the exposure of U.S. residents to these nominated substances. An integral part of the review process is the solicitation and consideration of public comments during the nomination and review process. Public comments are solicited three times during the steps involved in the review of a compound for possible listing in the RoC. Comments received during the course of a review become part of the public record and are provided to the review committees prior to their review as part of the review process. Note that the sequential nature of this process results in comments accumulating such that the final peer-review group has all of the available comments whereas the initial review group will only have comments that were submitted early in the review process.

The process outlined above was followed for the nickel compounds, metallic nickel and nickel alloys nominations. Several public comments were received regarding the evaluation of nickel compounds, metallic nickel and nickel alloys. In addition to others, comments were provided to the NTP by the Nickel Development Institute (NiDI), the Nickel Producers Environmental Research Association (NiPERA), and Inco, United States, Inc. (Inco) during the course of these reviews. Many of the comments outlined in your letter are identical to comments received from NiDI, NiPERA and Inco. As is our policy, these comments were considered by the review committees in their reviews of these nominations.

In contrast to the background document, the summary profiles for the new listings in the 10th RoC were prepared based on the information in the background documents, the public comments and the deliberations from the review committees. As the Introduction to the 10`hRoC states, the summary profile "contains a brief description of each substance with a summary of evidence for its carcinogenicity. These profiles are in alphabetical order, and they include specific references to the original papers used to support the listing of the substance." The summary profiles for Nickel Compounds and Metallic Nickel begin on page 111-162 in the 10th RoC, which is available electronically on the web at or can be ordered in hardcopy or CD from EHP Online (866-541-3841; 919-653-2595 e-mail:

The background documents for Nickel Compounds and Metallic Nickel should be considered as supporting documentation for the information in the summary profiles in the RoC. We feel that many of the concerns mentioned in your request for correction are addressed in the background documents. Based on your expressed concerns, we recognize that the link between the background document and the summary profile in the RoC may be unclear to many readers of the RoC. We plan to revise the Introduction in future editions of the RoC to clarify the relationship between these two documents.

You state in your letter the NTP failed to acknowledge that there is no evidence of carcinogenicity of nickel compounds by relevant routes of exposure other than inhalation. Route of exposure is one consideration when reviewing the data for listing in the RoC, but demonstration of carcinogenicity by one route of exposure has traditionally been sufficient for the purposes of listing a substance, and the listing criteria do not require demonstration of carcinogenicity by multiple routes of exposure to experimental animals or humans. For the nickel compounds listing, experimental animal studies by the inhalation route are appropriate as inhalation is a major route of exposure to humans. The additional experimental animal data by the subcutaneous, intramuscular, intraperitoneal, subperiosteal, intrafemoral, intrapleural, intracerebral, intrarenal, intratesticular, and intraocular injections of nickel compounds all have caused malignant tumors and contribute to the weight of the evidence for the carcinogenicity of nickel compounds and support the human epidemiology findings and the findings of the animal inhalation studies. As indicated above, the background documents prepared for the review of the metallic nickel and the nickel compounds nominations contained a discussion of all relevant studies, both positive and negative by the reported routes of administration that could be found in the peer-reviewed scientific literature. The background document provides the bulk of the information that serves as the basis for the recommendations of the review committees and ultimately the listing in the RoC.

You state in your letter that the 10th RoC is misleading in its failure to make clear that the "reasonably anticipated" listing of metallic nickel depends on the physical form in which the nickel metal is present. The Introduction to the 10th RoC addresses this issue by stating: "The substances listed in the RoC are either known or are reasonably anticipated to cause cancer in humans under certain exposure circumstances. In many cases, cancers resulting from exposures to the listed substances may require exposures for prolonged periods of time." It goes on to state: "The carcinogenic hazard that listed substances pose to any one person depends on many factors. Among these are the amount and duration of exposure to the substance, an individual's susceptibility to the carcinogenic action of the substance, and the intrinsic carcinogenicity of the substance. Because of these considerations, the RoC does not attempt to rank substances according to the relative carcinogenic hazards." The contrast you raise between massive solids of metal versus inhaled particles is inappropriate for the RoC and is the purview of regulatory agencies who must address the form and level of exposure that constitutes an unacceptable risk.

You note that the NTP makes no reference to the negative NTP experimental animal studies of nickel sulfate hexahydrate. This study is fully reviewed in the background document so your comment must pertain to the summary profile. As noted above, the summary profile contains a brief description of the data supporting the listing, not a complete presentation of all of the evidence; this is presented in the background document. The RoC review committees used the nickel compounds background document that contained all relevant human and animal study data, both positive and negative, as the basis for their discussions and recommendations for listing nickel compounds in the 10th RoC. The committees observed that the relation between solubility and carcinogenicity of nickel compounds had to do with higher toxicity of the soluble compounds combined with the low residence time of the nickel ions within organs. The review committees indicated their evaluation of the data on exposure concentrations for soluble and insoluble nickel from the various epidemiological investigations and the experimental animal inhalation studies indicated that toxicity and carcinogenicity of soluble nickel compounds present a problem of a similar magnitude as the insoluble nickel compounds.

The fourth point in your discussion notes that an "example of inaccuracy in the document is the statement that the Andersen, et al. (1996) study of nickel refinery workers in Norway showed that exposures to "soluble nickel alone " resulted in excess cancer risks." The complete statement about the Andersen study in the 10th RoC profile for nickel compounds states: "An additional study has shown that exposure of nickel refinery workers to soluble nickel compounds alone or in combination with other forms of nickel results in significant excess risks for lung and nasal cancer and that smoking and nickel exposure have a multiplicative effect (Andersen et al. 1996)." The statement in the 10thRoC is accurate. With regard to the Pang et al (1996) short report you refer to, this paper was not included in the background document because of a combination of limitations of the study. These include short periods of exposed work and the lack of occupational hygiene data relating to nickel exposure. The authors point out these and other shortcomings of the study in their discussion and state they feel "confident interpretation of the lung cancer findings is not possible..."

Regarding the fifth point in your letter, you state: "inaccuracies occur in the discussion of welding studies, which the 10th RoC cites as examples of occupations where exposure to nickel compounds can be viewed as causing increased cancer risks," and imply that the discussion of the Simonato et al. (1991) paper is incomplete. The 10th RoC profile for nickel compounds states: "Nickel exposure in mild-steel welders is associated with cancer (carcinoma) of the trachea, bronchus, and lung in some cases (Simonato et al., 1991), although subjects in these studies also were exposed to the known carcinogen chromium, which complicates the results." The nickel compound background document points out that the cohort in the Simonato paper included "shipyard welders, mild steel welders and those who had ever welded stainless steel" and goes on to say that stainless steel welders would have been exposed to a much higher level of nickel and chromium than those welding mild steel. The statement in the summary profile is accurate and reflects what has been reported in the literature.

The other papers you refer to (Gerin et al, 1993; Moulin et al, 1993; Danielsen et al, 1996; Hansen et al, 1996; and Moulin et al, 1997) discuss studies of stainless steel and/or mild steel welders or stainless steel producing workers and all identify an increased lung cancer risk. The Moulin et al, 1997 paper is noteworthy as it is a meta-analysis of most of the earlier studies and reports a 30-40% increase in the relative risk of lung cancer among welders. As you point out and as the background document and summary profile for nickel compounds indicate, the data from the studies of welders are complicated by co-exposures to other carcinogens. In addition, most papers do not contain data on the level of nickel exposure from the welding fumes. The data from these studies raise several interesting issues concerning cancers identified in welders and may be an occupational exposure that the NTP should review for possible listing in the RoC.

In your sixth point, you describe as grossly misleading the 10th RoC's characterization of the available human studies as being "inadequate" for evaluating the carcinogenic effects of metallic nickel in humans. In the overall evaluation of the epidemiologic studies that refer to metallic nickel, the review committees concluded these studies had cohorts with low power for detecting a direct effect of metallic nickel. Such low power results from either very limited exposure or a small number or exposed workers. The studies were also limited in the ability to evaluate the effects of exposure specific for metallic nickel, because the populations were also exposed to other potential carcinogens and/or other forms of nickel, including oxidic, sulfidic, and soluble nickel. No study of nickel workers published since the IARC monograph was published in 1990 has included workers exposed exclusively or even predominantly to metallic nickel or nickel alloys. Therefore, the review groups felt there were no epidemiological studies of exposed workers adequate for an evaluation of the carcinogenicity of metallic nickel or nickel alloys.

You provide references for papers to support your observation that over 40,000 workers from various nickel-using industry sectors have been examined for evidence of carcinogenic risk due to exposure to metallic nickel and, in some instances, accompanying oxidic nickel compounds. The studies reported in these papers were limited in power to detect an effect and/or they could not separate the effects of metallic nickel from exposure to other nickel compounds and/or other carcinogens. Of the et al., 1998). The sizes of the other studies you identify are relatively small. The study by Arena et al. (1998) includes workers from the Enterline and Marsh (1982) cohort. In terms of respiratory cancer, the number of exposed cases is relatively low in the studies by Cragle et al., 1984, Enterline and Marsh 1982, and Cox et al. 1981). The study by Enterline and Marsh provides some evidence of a dose-response relationship for nickel exposures and lung cancer (highest risk found in highest exposed individuals); however, this relationship is based on a small number of exposed subjects for each exposure level. Excess of cancer at other sites (for example, buccal cavity and pharynx cancer was reported by Cragle et al., 1984, sinonasal cancer by Enterline and Marsh 1982 and soft tissue carcinoma by Cox et al., 1981) were reported in some papers, but again the interpretation of this data is difficult due to the small number of exposed cases. While the study by Arena et al. 1998 has a large number of exposed cases, exposures levels were low, thus limiting the power to detect an effect. Moreover, the findings of this study are difficult to interpret because a significant excess of lung cancer was observed in high metal alloy white male workers when

compared to the total U.S. population, but not when compared to local populations. In this same study, an excess of lung cancer was found in female high nickel alloy workers compared to the total U.S. population (SMR =1.31, 95% CI=0.96 to 1.74, 47 exposed cases) and the local population (SMR=1.24, 95% CI =0.93 to 1.64, 47 exposed cases). There was also a significant increase in colon cancer mortality in non-white workers when compared to both the U.S. and local populations. Lastly, as mentioned above, many of these studies were not able to separate the effects of exposure to metallic nickel from exposure to nickel oxides and/or other nickel compounds (Cox et al., 1981, Cragle et al., 1984, and Enterline and Marsh 1982) or from other known or potential carcinogens (Moulin et al., 2000). Therefore, while the total number of workers studied in these papers was not inconsequential, the results are not adequate for the evaluation of carcinogenicity of metallic nickel in humans.

Your seventh point concludes that the exposure information for the average daily oral intake of nickel is inaccurate. As you indicate in your letter, we used the most recent Hazardous Substances Data Bank (HSDB 2001) to provide exposure estimates. The HSDB is an accepted, authoritative source of information for the daily oral intake of nickel. The information from the ATSDR (1997) suggesting this value is now considered to be -168 mg/day will be noted in the next edition of the RoC.

The last three points of your discussion (#8, 9, & 10) imply that the regulations section of the summary profile for metallic nickel and nickel compounds contains several inaccuracies or mistakes. Our process for developing regulatory summaries includes review by the Federal agencies responsible for these regulations (e.g., EPA). As per our procedures, the regulatory sections of the metallic nickel and the nickel compounds summary profiles in the 10 RoC were reviewed by the appropriate agencies and revised according to their comments. Because of your concern, we will return the metallic nickel and the nickel compounds summary profiles to the appropriate agencies and ask them to review your comments and to determine if these profiles contain mistakes or inaccuracies. If mistakes or inaccuracies are identified, they will be corrected accordingly in the next edition of the RoC.

In response to your statement that the 10th RoC fails to comply with the science quality principles established by congress in the Safe Drinking Water Act Amendments of 1996, I would point out that the Office of Management and Budget (OMB) Guidelines state: "With regard to analysis of risks to human health, safety and the environment maintained or disseminated by the agencies, agencies shall either adopt or adapt the quality principles applied by Congress to risk information used and disseminated pursuant to the Safe Drinking Water Act Amendments of 1996 (42 U.S.C. 300g- 1(b)(3)(A) & (B))." See 67 FR 8452, 8460 (February 22, 2002) (emphasis added). The RoC is not a risk assessment document and does not address risks associated with exposures to the listings contained in the report. As stated in the Introduction to the 10th RoC: "The Report on Carcinogens (RoC) is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. It serves as a meaningful and useful compilation of data on (1) the carcinogenicity (whether it causes cancer), genotoxicity (whether it causes damage to genes), and biologic mechanisms (how it works in the body) of the listed substances in people and/or in animals, (2) the potential for human exposure to these substances, and (3) Federal regulations to limit exposures. The RoC does not present quantitative assessments of the carcinogenic risk of these substances. Listing of substances in the RoC, therefore, does not establish that these substances present carcinogenic risks to individuals in their daily lives. Such formal risk assessments are the responsibility of the appropriate federal, state, and local health regulatory and research agencies." (Emphasis added). Thus, as the agency makes plain in the Introduction to the RoC, the information contained in the document is not an analysis of risks that would trigger application of the Safe Drinking Water Act quality principles under the NIH Guidelines or the OMB Guidelines. The information contained in the RoC fully satisfies all applicable objectivity standards under these guidelines.

Finally, you state that the 10th RoC overemphasizes two animal studies that have little or no relevance to potential human cancer risk. The Karprzak et al. (1990) study indicates that soluble nickel is an effective initiator of the carcinogenic process in the kidney. Note that tumors were not observed in female rats in this study because no female rats were used in this study. The second study you refer to was reported by Diwan et al. (1992) who investigated the transplacental carcinogenic effects of nickel(II) acetate in rats. Malignant pituitary tumors occurred in rats given nickel acetate alone and also those given nickel acetate with the barbital promoter, and the pituitary tumor incidence was elevated in both sexes given nickel acetate prenatally. These pituitary tumors induced with this soluble nickel salt were malignant, in marked contrast to the benign nature of most spontaneous pituitary tumors observed in rats. Since the pituitary tumors were observed in the animals treated not only with nickel acetate and the barbital promoter but, more importantly, with nickel acetate alone, these studies provide additional evidence that soluble nickel compounds are potent, complete adult and transplacental carcinogens.

In summary, the 10th RoC summary profiles for metallic nickel and for nickel compounds comply with requirements of the Data Quality Act as implemented by OMB, Health and Human Services and NIH. The NTP appreciates your bringing to our attention additional information about daily intakes of nickel and possible mistakes in the cited regulations. As noted above, we will review this information in accord with existing procedures for ensuring its quality and, if necessary, make revisions in the next edition of the report.

I would like to let you know that you may appeal the agency's decision either in writing or electronically within 30 days of receiving this response. Your request should state the reasons for your appeal. It does not need to reference a tracking number. The request may be sent electronically to or in hard copy to the Associate Director for Communications, Office of the Director, National Institutes of Health, Building 1, Room 344, 1 Center Drive, Bethesda, Maryland 20892. If the appeal is sent in hard copy, please clearly mark the appeal and outside envelope with the phrase "Information Quality Appeal."


Christopher L. Portier, Ph.D. 
Associate Director 
Nation Toxicology Program

1These guidelines were issued pursuant to, and are consistent with: (1) the Department of Health and Human Services "Guidelines for Ensuring and Maximizing the Quality, Objectivity, Utility, and Integrity of Information Disseminated to the Public" (HHS Guidelines); (2) the Office of Management and Budget "Guidelines for Ensuring and Maximizing the Quality, Objectivity, Utility, and Integrity of Information Disseminated by Federal Agencies" (OMB Guidelines); and (3) section 515 of the Treasury and General Government Appropriations Act for Fiscal Year 2001.

Last Revised:  August, 2004