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A nested case-control study of serum concentrations of per- and polyfluoroalkyl substances and thyroid cancer risk among military aviators and aviation support personnel

Principal Investigator

Name
Jonathan Hofmann

Degrees
PhD, MPH

Institution
National Cancer Institute

Position Title
Senior Investigator

Email
hofmannjn@mail.nih.gov

About this CDAS Project

Study
MACS (Learn more about this study)

Project ID
2026-0134

Initial CDAS Request Approval
Sep 24, 2026

Title
A nested case-control study of serum concentrations of per- and polyfluoroalkyl substances and thyroid cancer risk among military aviators and aviation support personnel

Summary
Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals that have been widely used in a variety of industrial and consumer applications, including aqueous film-forming foams (AFFFs) used by firefighters to suppress petroleum-related fires. Many PFAS are highly persistent in the environment and bioaccumulate in humans, with biological half-lives ranging from approximately 2-8 years. Since the 1970s, AFFFs containing perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and other PFAS have been routinely used at U.S. military installations. Systematic testing by the Department of War (DoW) has identified 401 military facilities with known or suspected releases of PFOS or PFOA, including 126 bases where PFOA/PFOS concentrations in drinking water or groundwater exceeded current safety guidelines.

In 2023, the International Agency for Research on Cancer (IARC) classified PFOA as carcinogenic to humans (Group 1) and PFOS as a possible human carcinogen (Group 2B), based on sufficient evidence in experimental animals, strong mechanistic evidence in exposed humans, and (for PFOA) limited epidemiologic evidence for cancers of the kidney and testis. Toxicologic and molecular epidemiologic findings demonstrate that PFAS exhibit multiple key characteristics of carcinogens, including the induction of oxidative stress, immunosuppression, epigenetic alterations, cell proliferation, and modulation of receptor-mediated effects. In particular, many PFAS exhibit endocrine-disruption properties, suspected to play a role in thyroid carcinogenesis.

Studies in highly PFAS exposed populations, including the C8 Science Panel cohort and a community in Ronneby, Sweden, have reported suggestive associations between PFAS exposure and thyroid cancer risk. However, prospective studies conducted in cohorts with exposure levels comparable to those observed in the general U.S. population have produced mixed results. Despite the unique occupational exposure potential among military personnel, the impact of PFAS exposure on thyroid cancer risk in this population remains insufficiently studied.

The Military Aviators Cancer Study (MACS), a Congressionally mandated cohort of U.S. military aircrew (N=156,050) and groundcrew (N=737,891), reported a 31% increase of thyroid cancer risk among aircrew compared with demographically similar individuals in the U.S. population (standardized incidence ratio [SIR]: 1.31, 95% confidence interval [CI]: 1.16-1.46). The underlying reasons for this excess risk remain unclear. Given documented PFAS contamination at military installations and the biological plausibility linking PFAS to thyroid carcinogenesis, PFAS represent a compelling yet understudied risk factor.

We propose to investigate the association between pre-diagnostic serum PFAS concentrations and thyroid cancer risk among military aviators and aviation support personnel in the MACS using stored serum samples collected during active service.

This proposed study directly aligns with the Phase 2 objectives of evaluating cancer risk associated with toxic and hazardous exposures. Specifically, it aims to identify occupational and environmental chemical exposures that may contribute to the 31% excess incidence of thyroid cancer among military aircrew compared with demographically similar individuals in the general U.S. population. These exposures include those related to flight operations at shipboard or land-based facilities (e.g., fuels, fumes, and other operational materials), as well as environmental contaminants present in water and soil on military bases and in housing facilities.

Aims

The primary aims of our proposed project are:

1. To investigate the associations between pre-diagnostic serum concentrations of PFAS and thyroid cancer risk diagnosed among military aircrew and groundcrew; and

2. To assess thyroid cancer risk in relation to other exogenous chemical exposures and endogenous metabolic perturbations.

We hypothesize that 1) exposure to individual PFAS and PFAS mixtures is associated with increased thyroid cancer risk, and 2) additional exogenous and endogenous metabolites may influence thyroid cancer risk.

In addition to these primary aims, we also propose addressing the following secondary aims:

1. To examine the association between pre-diagnostic serum concentrations of PFAS and thyroid cancer risk by histologic subtype, stage at diagnosis, and tumor size;

2. To assess differences in the relationship between pre-diagnostic serum PFAS concentrations and thyroid cancer risk by study group (aircrew, groundcrew) and other population characteristics (e.g., age, sex, race and ethnicity);

3. To explore metabolic perturbations and related pathways through which PFAS and other chemical exposures may influence risk of thyroid cancer; and

4. To identify the potential determinants of serum PFAS concentrations in relation to job duties, service history, and other factors.

PFAS exposure is a significant concern for military aviators and aviation support personnel. U.S. Air Force servicemen working in fire protection occupations have been shown to have elevated blood concentrations of several AFFF-related PFAS. In addition, decades of AFFF use have contaminated groundwater and drinking water on many air bases, raising concerns about chronic exposure through ingestion. Notably, data from the 2016-2017 DoW PFAS water testing survey indicate that 203 of 401 military installations with a known or suspected release of PFOA/PFOS were Air Force bases. However, evidence regarding associations between PFAS exposure and thyroid cancer among military personnel remains limited. The ongoing study conducted by AFHSD to investigate the association between pre-diagnostic serum concentrations of PFAS exposure and thyroid cancer risk only includes cases diagnosed during active service. Given that the median age at diagnosis of thyroid cancer is 51 years and that there may be a long latency between PFAS exposure and thyroid cancer development, it is likely that most thyroid cancers would be missed when relying solely on cancer diagnoses occurring during active duty status. In contrast, the MACS provides a unique opportunity to evaluate PFAS exposures during an etiologically relevant time period, including for cases diagnosed after separation from active duty.

Beyond PFAS, military aviators and aviation support personnel are likely exposed to a range of additional potential carcinogens, including jet propulsion fuels, diesel exhaust, industrial solvents, and certain pesticides. Additionally, thyroid hormone homeostasis may affect the association between PFAS exposure and thyroid cancer risk. To address this complexity, the proposed study incorporates an untargeted metabolomics approach (Aim 2), which will enable quantitation of a diverse array of exogenous chemical exposures and endogenous metabolites. This approach will enhance our ability to identify novel exposure-disease relationships and better understand the broader “exposome” reflecting an array of chemical pollutants that may be relevant to thyroid cancer risk in this population.

Collaborators

Jonathan Hofmann (National Cancer Institute)
Mark Purdue (National Cancer Institute)
Eun Mi Jung (National Cancer Institute)
Cari Kitahara (National Cancer Institute)
Karl Alcover (Uniformed Services University Health Services)