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Sex modifies response to ozone and nitrogen dioxide: a controlled human exposure study
Jairus C Pulczinski1, Ana G Rappold1, Robert B Devlin1
1Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, Chapel Hill, NC, USA.
Inhalation Toxicology
|November 17, 2025
Summary
This study reveals that sex influences how the body responds to ozone (O3) and nitrogen dioxide (NO2) pollution. Males and females exhibit distinct pulmonary and inflammatory reactions to these harmful gases.
Area of Science:
- Environmental Health
- Toxicology
- Pulmonary Medicine
Background:
- Ozone (O3) and nitrogen dioxide (NO2) are air pollutants linked to increased mortality.
- Epidemiological studies suggest sex-specific risks associated with O3 and NO2 exposure, impacting pulmonary function and cardiovascular disease (CVD).
- Existing research indicates females exhibit stronger associations with CVD and lung function decline from NO2, while O3 affects males' pulmonary function more severely and females' CVD risk.
Purpose of the Study:
- To investigate sex-specific differences in pulmonary, inflammatory, and clotting/fibrinolysis responses following controlled exposure to O3 and NO2.
- To compare these responses against a clean air control in healthy adults.
- To determine if biological mechanisms underlie observed sex differences in pollutant response.
Main Methods:
- A single-blind, randomized crossover controlled exposure study design was employed.
- Healthy adult participants (n=22; 10 male, 12 female) underwent separate two-hour exposures to clean air, 300 ppb O3, and 500 ppb NO2.
- Pulmonary function tests, inflammatory markers (IL-6, CRP, SAA, TNFα), and clotting/fibrinolysis markers (D-dimer) were assessed.
Main Results:
- Ozone exposure led to significant decrements in FEV1, FVC, and FEV1/FVC, along with elevated IL-6, CRP, and SAA compared to clean air.
- Nitrogen dioxide exposure showed a trend towards increased D-dimer.
- Sex-stratified analysis revealed males experienced greater FEV1 decline and CRP/SAA increases after O3 exposure, while females showed elevated TNFα. After NO2, females exhibited a trend towards higher D-dimer levels compared to males.
Conclusions:
- Sex significantly modifies the pulmonary and inflammatory responses to acute ozone and nitrogen dioxide exposure.
- These findings align with epidemiological observations of sex differences in health outcomes following air pollution exposure.
- The study highlights the importance of considering sex as a biological variable in air pollution research and risk assessment.
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