Table 4.

Summary of available studies evaluating immune effects.

Author and publication year	Study description	Route of exposure	Exposure measurement	Outcome(s) evaluated	Outcomes(s) observed	Overall confidence level for outcome	Applicability for dose–response
Human studies (inhalation)
Rhodes et al. (2003)	Occupational cross-sectional study of 151 subjects from 3 U.S. Air Force bases, age 18–44 y in United States (southeastern states)	Inhalation	Naphthalene levels in breathing zone air during 4-h work assignments.	Immune cell counts in peripheral blood (total and differential leukocyte counts, total lymphocytes, T-cells, T-helper cells, T-suppressor cells, natural killer cells, B cells)	Statistically significantly higher counts of total leukocytes, neutrophils, and monocytes in high versus low/no exposure groups	Medium. All domains were evaluated as at least adequate.	Limited suitability. Cross-sectional study with limited ability to assess temporality.
Lehmann et al. (2002)	General population cohort study of 85 randomly selected newborns (43 boys and 42 girls) in Leipzig, Germany	Inhalation	Naphthalene levels in air samples collected during a 4-wk period in bedrooms of 3-y-olds and used as a proxy for maternal exposure	Cytokine secretion profiles of cord-blood T cells (IL-4, IL-2, $\text{interferon-}\mathrm{\gamma }$, and tumor necrosis factor $\mathrm{\alpha }$)	Statistically significant positive association with elevated percentages of IL-4–producing type 2 T cells	Low. The exposure measures and confounding domains were evaluated as deficient.	Limited suitability. Postnatal exposure measurements may not be a viable proxy for prenatal/maternal exposure.
Lehmann et al. (2001)	General population cohort study of 200 3-y-old children in Leipzig, Germany	Inhalation	Naphthalene levels in air samples collected during a 4-wk period in bedrooms of 3-y-olds	Sensitization to allergens, measured as total serum IgE and specific IgE antibodies to food (milk, egg), indoor (cat, D. pteronyssinus, D. farina, Penicillium notatum, Aspergillus fumigatus, and Candida albicans), and outdoor (birch, timothy) allergens. Cytokine-producing peripheral T cells were measured in a subgroup of $n=28$ children.	Higher prevalence of allergic sensitization in VOC-exposed groups (including naphthalene); statistically significantly relationship with decreased $\text{CD}8+$ peripheral T cells	Low. The confounding domain was evaluated as deficient and considered to have a severe impact on the interpretation of results.	Limited suitability. Exposure information was only available for 60% of subjects. High association between naphthalene and other VOCs is a potential confounder.
Human studies (nonspecific route of exposure)
Lin et al. (2018)	General population cross-sectional health survey of 453 kindergarten children from the Childhood Environment and Allergic Diseases Study cohort in Taiwan	Nonspecific route of exposure	Urinary metabolite levels (2N)	Serum IgE levels and allergic diseases (atopic dermatitis, allergic rhinitis, and asthma)	Statistically significant association with asthma	Medium. All domains except participant selection were evaluated as at least adequate.	Limited suitability. Cross-sectional study design with limited ability to assess temporality. Also, insufficient availability of data or models to relate urinary metabolites to exposure levels.
Al-Daghri et al. (2013)	General population cross-sectional study of children $\le 15\mathrm{y}\text{\hspace{0.17em}old}$ (98 asthma patients, 97 healthy controls) in Saudi Arabia.	Nonspecific route of exposure	Naphthalene levels in serum	Asthma-related biomarkers (e.g., resistin, cytokines, serum immunoglobins)	Statistically significant correlation of asthma biomarkers with serum naphthalene levels	Low. Domains on participant selection, exposure measures, confounding, and analysis were evaluated as deficient.	Limited suitability. Cross-sectional study with limited ability to assess temporality. Study does not adjust for possible confounders or interaction with other measured PAHs.
Al-Daghri (2008)	General population cross-sectional study of children $\le 5\text{\hspace{0.17em}years}$ of age (61 asthmatic, 14 nonasthmatic cases) in Saudi Arabia.	Nonspecific route of exposure	Naphthalene levels in serum	Diagnosis of asthma	Statistically significantly higher mean serum naphthalene levels in asthma cases versus nonasthmatic cases	Low. Domains on participant selection, confounding, and analysis were evaluated as deficient.	Limited suitability. Cross-sectional study with limited ability to assess temporality.
Kim et al. (2005)	General population case–control study of children identified at Pediatric Allergy Clinic; 30 asthma cases (20 male, 10 female, mean age 4.9 y) and 30 controls with no history of wheezing episodes or allergic disease (13 male, 17 female, mean age 5.5 y) in Korea	Nonspecific route of exposure	Urinary metabolite levels (2N)	Diagnosis of asthma	No significant difference in urinary naphthalene metabolite levels in control vs. asthmatic groups	Low. Domains on participant selection, exposure measures, analysis, and sensitivity were evaluated as deficient.	Limited suitability. Insufficient availability of data or models to relate urinary metabolites to exposure levels.
Animal studies (inhalation)
Dodd et al. (2012)	Male and female rats (Fischer 344); 90-d exposure	Inhalation (whole body)	0, 0.5, 5.2, 52, $157{\mathrm{mg}/\mathrm{m}}^3$	Thymus and spleen weights	Statistically significant decrease in thymus weight in both sexes and spleen weight in males	High. This study was well-designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
NTP (2000)	Male and female rats (Fischer 344); 2-y (105-wk) exposure	Inhalation (whole body)	0, 52, 157, $314{\mathrm{mg}/\mathrm{m}}^3$	Histopathology of lymph nodes (mandibular, mesenteric, bronchial, and mediastinal), thymus, and spleen	No effects observed	High. This study was well designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.
NTP (1992b)	Male and female mice (B6C3F1); 2-y (103-wk) exposure	Inhalation (whole body)	0, 52, $157{\mathrm{mg}/\mathrm{m}}^3$	Histopathology of lymph nodes (mandibular, mesenteric, bronchial, and mediastinal), thymus, and spleen	No effects observed	High (females). This study was well designed to evaluate these outcomes. Evidence was presented clearly and transparently. Low (males). The high mortality rate in control males has the potential to interfere with the interpretation of results.	Suitable. Multidose study with quantitative data.
Animal studies (oral)
Battelle (1980b)	Male and female rats (Fischer 344); 90-d exposure	Oral gavage	0, 25, 50, 100, 200, $400\mathrm{mg}/\mathrm{kg}-\mathrm{d}$	Histopathology of thymus and spleen	Moderate depletion of thymic lymphocytes in females	High. This study was well designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose studies with quantitative data.
Battelle (1980a)	Male and female mice (B6C3F1); 90-d exposure	Oral gavage	0, 12.5, 25, 50, 100, $200\mathrm{mg}/\mathrm{kg}-\mathrm{d}$	Histopathology of thymus and spleen	No effects observed	High. This study was well designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose studies with quantitative data.
Shopp et al. (1984)	Male and female mice (CD-1); 14- or 90-d exposure	Oral gavage	14-d exposure: 0, 27, 53, $267\mathrm{mg}/\mathrm{kg}-\mathrm{d}$ 90-d exposure: 0, 5.3, 53, $133\mathrm{mg}/\mathrm{kg}-\mathrm{d}$	Immunotoxicity assays including antibody forming cell counts, lymphocyte responsiveness, analysis of delayed-type hypersensitivity and popliteal lymph node response, and bone marrow function; thymus and spleen weights	14-d exposure: Statistically significant decrease in absolute thymus weight in males and absolute and relative spleen weight in females 90-d exposure: Statistically significant decrease in absolute and relative spleen weight in females	High (organ weights). This study was well-designed to evaluate these outcomes. Evidence was presented clearly and transparently. Medium (immunotoxicity assays). This study was well-designed to evaluate these outcomes, but confidence was decreased because only qualitative results are provided.	Suitable (organ weights). Multidose study with quantitative data. Not suitable (immunotoxicity assays). Data not shown for 14-d study; qualitative data is presented for 90-d study.
Animal studies (dermal)
Bushy Run (1986)	Male and female rats (Sprague-Dawley CD); 90-d exposure	Dermal	0, 100, 300, $\mathrm{1,000}\mathrm{mg}/\mathrm{kg}-\mathrm{d}$	Histopathology of thymic region, spleen, and lymph nodes	No effects observed	High. This study was well designed to evaluate these outcomes. Evidence was presented clearly and transparently.	Suitable. Multidose study with quantitative data.

Note: IL, interleukin.