RHP Risk Management researchers have published a new analysis examining the potential carcinogenicity of hydrochloric acid (HCl) in the peer-reviewed publication Journal of the Air & Waste Management Association. The open-access manuscript, “Health-based emissions limits: Integrating evidence for threshold vs. non-threshold health effects using HCl as an example,” is currently in press, and available on the journal’s web site at tandfonline.com.

Authored by Drs. Debra A. Kaden, Thomas J. Luben, Melanie C. Buser, and Sandra I. Sulsky, the paper uses HCl to explore a consequential risk-assessment question: When does the available evidence support a linear, no-threshold model, and when does it instead support a threshold below which any potential cancer risk is not expected?

Why the dose-response model matters

For many carcinogens, risk assessment has historically relied on the protective default assumption that risk increases linearly with dose and that no exposure is entirely without risk. That approach is particularly relevant when a chemical directly damages DNA. It may not accurately describe every chemical or every cancer mechanism, however.

Some biological processes associated with cancer – including sustained tissue irritation, cytotoxicity followed by regenerative cell proliferation, endocrine activity, and other indirect mechanisms – can depend on exceeding a level at which normal protective or repair processes are overwhelmed. For these substances, understanding mode of action and exposure context is essential to selecting an appropriate dose-response model. For other substances, the question of whether the substance is a carcinogen or not has not been definitively answered, leading regulation as a potential carcinogen with the default assumption of linearity.

The question is not whether threshold models should replace linear models broadly. It is whether the model used for a particular chemical and health endpoint is supported by the totality of the evidence.

What the HCl review found

The authors evaluated 34 relevant studies across epidemiology, chronic animal bioassays, and genotoxicity. Several findings were important to the overall weight of evidence:

• The epidemiologic literature was limited and methodologically constrained. Studies with more specific HCl exposure assessment generally reported null results, but the evidence base was not strong enough to establish or exclude associations for every cancer outcome.
• The chronic animal studies reviewed did not provide evidence that HCl exposure caused cancer.
• Gene-mutation studies were largely negative. Positive chromosome-level findings occurred mainly under highly acidic, cytotoxic laboratory conditions and were consistent with effects of severe pH disruption rather than direct DNA reactivity.
• Taken together, the evidence did not support a direct mutagenic or systemic carcinogenic mode of action for HCl and was consistent with the scientific plausibility of a threshold for effects driven by local acidity, irritation, and cytotoxicity.

In fact, the available evidence does not support HCl being carcinogenic, further strengthening the argument for a threshold approach to toxicity. Even if it were carcinogenic, which the evidence does not support, the paper points out that the only potential cancer-related effects observed (chromosome-level genotoxicity) occurred at environmentally irrelevant exposures. This highlights that experimental context can change the interpretation of observed effects.

HCl illustrates why a positive result (chromosome-level genotoxicity) should not be interpreted without examining the conditions that produced it. In several in vitro studies, chromosome-level effects appeared only after the test system became unusually acidic and cytotoxic. Those conditions can disrupt cell division, but they differ substantially from physiological conditions in which buffering systems tightly regulate pH. Taken together with the lack of evidence in epidemiologic studies, these findings do not support a conclusion of carcinogenicity.

This distinction is central to sound risk assessment: a hazard signal produced under extreme test conditions may identify a biological response without demonstrating that the same mechanism will operate at environmentally or occupationally relevant exposures. Exposure level, route, duration, tissue dosimetry, and biological plausibility all affect how a study should inform a real-world decision.

Relevance to Clean Air Act decisions

The analysis also has a practical regulatory context. HCl is listed as a hazardous air pollutant under the Clean Air Act. Section 112(d)(4) allows the U.S. Environmental Protection Agency to consider health-based emissions limits for pollutants that have an established health threshold, provided the standard includes an ample margin of safety.

EPA previously considered, but did not finalize, a health-based emissions limit for HCl in its rulemaking for lime manufacturing plants, explaining that additional time was needed to evaluate the evidence related to carcinogenicity and other scientific issues. The new paper contributes a transparent synthesis of the epidemiologic, animal, and mechanistic evidence relevant to that question.

Importantly, the authors distinguish the scientific assessment from the ultimate regulatory decision. Evidence that supports threshold behavior can inform an agency’s analysis, but it does not by itself resolve statutory interpretation, policy choices, implementation details, or the numerical value of an appropriate emissions limit.

Continuing the discussion at SRA 2026

RHP will bring this work to the Society for Risk Analysis 2026 Annual Meeting in Atlanta as part of the symposium “Thresholds for Carcinogens: Reconsidering a Foundational Assumption in Modern Risk Assessment.”

The symposium is scheduled for Wednesday, December 9, from 8:30 to 10:00 a.m. in International Salon 9 at the Atlanta Marriott Marquis. View the SRA session program.

Co-chaired by RHP Principal Toxicologist Dr. Debra Kaden and Dr. Nancy Beck of the U.S. Environmental Protection Agency, the session will examine how mechanistic evidence, mode of action, and exposure context can inform the selection of threshold or non-threshold approaches. Presentations will include:

• Dr. Debra Kaden, RHP Risk Management – an introduction to the scientific and regulatory questions surrounding thresholds for carcinogens;
• Dr. Amber Goetz, Syngenta Crop Science – use of the Rethinking Carcinogenicity Assessment for Agrochemicals Project framework to operationalize mechanistic carcinogenicity assessment;
• Dr. Katy Goyak, Celanese – the role of cell proliferation in formaldehyde-induced nasal tumors;
• Dr. Melanie C. Buser, RHP Risk Management – HCl as a case study in integrating mechanistic evidence and exposure context; and
• Dr. Anna Lowit, U.S. Environmental Protection Agency – use of the ReCAAP framework and mode-of-action information in EPA Toxic Substances Control Act risk evaluations.

Together, the manuscript and symposium advance the same practical principle: dose-response assumptions should be selected through chemical- and endpoint-specific evaluation, not applied solely by default. A defensible assessment integrates epidemiology, toxicology, mechanistic evidence, and realistic exposure conditions while clearly describing uncertainties and the limits of the available data.

How RHP can help

RHP’s Human Health Risk Sciences team supports organizations facing complex questions involving carcinogenicity, dose-response, regulatory toxicology, and exposure. Our scientists integrate systematic evidence review, epidemiology, mechanistic toxicology, benchmark dose analysis, and exposure assessment to develop transparent evaluations suited to the specific regulatory or decision context.

To discuss how RHP can support chemical hazard evaluation, risk assessment, regulatory strategy, or scientific communication, contact RHP Risk Management.

Research disclosure

The review was funded by the National Lime Association. As stated in the manuscript, the conclusions are those of the authors.