EPA IRIS 2024 — Toxicological Review of Hexavalent Chromium [Cr(VI)]
Summary
The August 2024 EPA IRIS Toxicological Review of Hexavalent Chromium is the current US federal toxicological assessment for Cr(VI), updating the 1998 IRIS assessment. It derives a chronic oral reference dose (RfD) of 9 × 10⁻⁴ mg/kg-day anchored on gastrointestinal hyperplasia in female mice, a chronic inhalation reference concentration (RfC) of 3 × 10⁻⁵ mg/m³ anchored on nasal-septum ulceration in occupational humans, an adult oral cancer slope factor (OSF) of 0.16 (mg/kg-day)⁻¹ (0.27 with age-dependent adjustment factors applied across lifetime exposure) based on oral-cavity squamous-cell tumors in female rats, and an adult inhalation unit risk (IUR) of 1.1 × 10⁻² (µg/m³)⁻¹ (1.8 × 10⁻² with ADAFs) based on lung cancer in a chromate-production worker cohort. Cr(VI) is classified as likely to be carcinogenic to humans by the oral route and carcinogenic to humans by the inhalation route. The assessment identifies neonates and infants under 30 months, individuals with chronically elevated stomach pH (hypochlorhydria, GERD-medication users), DNA-repair-deficient and CFTR-mutated populations, the developing fetus, and the elderly as susceptible groups for whom the standard RfD/OSF may under-protect.
Key numbers
Reference values for chronic exposure to Cr(VI):
| Route | Reference value | Critical effect | Critical study |
|---|---|---|---|
| Oral chronic RfD | 9 × 10⁻⁴ mg/kg-day | Diffuse epithelial hyperplasia in the duodenum of female B6C3F1 mice | NTP 2008 chronic drinking-water bioassay |
| Inhalation chronic RfC | 3 × 10⁻⁵ mg/m³ | Ulceration of the nasal septum in occupationally exposed humans | Gibb et al. 2000a |
Organ/system-specific oral RfDs from Table ES-1:
| Hazard | Basis | osRfD (mg/kg-day) | Confidence |
|---|---|---|---|
| Gastrointestinal (GI tract) | Hyperplasia in small intestine of female mice | 9 × 10⁻⁴ | Medium-High |
| Hepatic | Chronic inflammation in female rats | 7 × 10⁻⁴ | Medium-High |
| Developmental | Decreased F1 offspring postnatal growth | 0.07 | Low |
| Hematological | Decreased Hgb (male rats) | 0.01 | Medium |
| Overall RfD | GI tract effects | 9 × 10⁻⁴ | Medium-High |
Selected RfD-derivation points of departure from Table ES-2:
| Critical effect | POD (mg/kg-day) | UF | Candidate value (mg/kg-day) |
|---|---|---|---|
| Mouse (F) duodenum diffuse epithelial hyperplasia | LOAEL_HED 0.0911 | 100 | 9.11 × 10⁻⁴ |
| Mouse (M) duodenum diffuse epithelial hyperplasia | BMDL_10%ER-HED 0.0443 | 10 | 4.43 × 10⁻³ |
| Rat (F) liver chronic inflammation (2 yr) | LOAEL_HED 0.0669 | 100 | 6.69 × 10⁻⁴ |
| Mouse (F) decreased F1 postnatal growth | NOAEL_HED 0.700 | 10 | 0.0700 |
| Rat (M) decreased Hgb (22 d) | BMDL_1SD-HED 0.126 | 10 | 0.0126 |
Inhalation RfC derivation from Table ES-4 (upper-respiratory-tract toxicity):
| Critical effect | LOAEL (mg/m³) | UF | Candidate (mg/m³) | osRfC (mg/m³) |
|---|---|---|---|---|
| Ulceration of the nasal septum (Gibb et al. 2000a) | 3.4 × 10⁻³ | 100 | 3.4 × 10⁻⁵ | 3 × 10⁻⁵ |
| Nasal mucosal pathology (Cohen et al. 1974) | 9.5 × 10⁻⁴ | 100 | 9.5 × 10⁻⁶ | |
| Ulceration of the nasal septum (Lindberg and Hedenstierna 1983) | 6.6 × 10⁻⁴ | 100 | 6.6 × 10⁻⁶ |
Oral cancer slope factor (OSF) derivation from Table ES-5:
| Critical effect | Point of departure (mg/kg-day) | HED (mg/kg-day) | Adult OSF (mg/kg-day)⁻¹ | Confidence |
|---|---|---|---|---|
| Adenomas/carcinomas in small intestine of male mice (NTP 2008) | BMDL_01%ER 0.0208 | 0.0931 | 0.107 | High |
| Adenomas/carcinomas in small intestine of female mice (NTP 2008) | BMDL_01%ER 0.0232 | 0.102 | 0.0980 | High |
| Oral-cavity SCC/SCP, male rats (NTP 2008) | BMDL_10%ER 3.37 | 0.923 | 0.108 | High |
| Oral-cavity SCC/SCP, female rats (selected) (NTP 2008) | BMDL_10%ER 2.70 | 0.645 | 0.155 → 0.16 | High |
Adult-exposure OSF (no ADAF) = 0.16 (mg/kg-day)⁻¹; lifetime OSF after age-dependent adjustment factors = 0.27 (mg/kg-day)⁻¹.
Inhalation unit risk (IUR) derivation from Table ES-6:
| Critical effect | Basis | Adult-exposure IUR | Lifetime IUR (with ADAFs) |
|---|---|---|---|
| Lung cancer | Gibb et al. 2020 chromate-production worker cohort, Baltimore MD | 1.1 × 10⁻² (µg Cr(VI)/m³)⁻¹ | 1.8 × 10⁻² (µg Cr(VI)/m³)⁻¹ |
Carcinogenicity hazard descriptors (per EPA 2005a Guidelines for Carcinogen Risk Assessment): Cr(VI) is likely to be carcinogenic to humans by the oral route (robust animal evidence, slight human evidence, strong mechanistic support; mutagenic mode of action sufficient in animals and relevant to humans), and carcinogenic to humans by the inhalation route (lung cancer in chromate-production cohorts).
Susceptible populations and life stages identified in Section ES.6:
- Individuals with pre-existing GI, liver, respiratory, or anemic disease whose endpoints overlap Cr(VI) effects.
- Individuals with chronically elevated stomach pH (hypochlorhydria, GERD medication use, population variability), which reduces gastric Cr(VI) → Cr(III) detoxification.
- Carriers of DNA-repair-capacity polymorphisms.
- Carriers of mutated CFTR alleles (impaired CFTR enhances intestinal tumorigenesis in animal models).
- The developing fetus in utero (developmental toxicity likely in humans).
- Neonates, infants, and toddlers younger than 30 months (elevated stomach pH limits Cr(VI) detoxification).
- Elderly populations (≥65 y) with comorbidities including elevated stomach pH.
Methods (brief)
EPA conducted a systematic review per the Cr(VI) IRIS Assessment Protocol (Appendix A) covering all cancer outcomes and noncancer effects across respiratory, GI, hepatic, hematological, immune, reproductive, and developmental target systems. For cancer and nasal-irritation endpoints by the inhalation route, the review focused on data that could improve the quantitative dose-response analysis from the 1998 IRIS assessment rather than re-derive hazard identification de novo. Human-equivalent doses (HEDs) for oral endpoints were calculated using PBPK modeling for endpoints downstream of gastric Cr(VI) reduction (small-intestinal tumors, GI hyperplasia) and using BW^(3/4) scaling for endpoints occurring prior to gastric reduction (oral-cavity tumors). The inhalation unit risk derivation used the Gibb et al. occupational chromate-production cohort with linear low-dose extrapolation from the BMDL and application of age-dependent adjustment factors per EPA 2005b Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens. Dose-response modeling used BMD methods where data were amenable; LOAEL-based PODs with composite uncertainty factors (typically UF_A=3, UF_H=3, UF_L=10) were used where BMD was not feasible. Confidence ratings (low/medium/medium-high/high) were assigned per the IRIS Handbook study-evaluation framework. The assessment notes substantial uncertainty in low-dose (<1 mg/kg-day) systemic Cr(VI) distribution because only total chromium can be measured in vivo in tissues, and most tissue Cr is Cr(III).
Implications
- Certification (HMTc): The 9 × 10⁻⁴ mg/kg-day oral RfD (= 0.9 µg/kg-bw/day) is the current US federal allowable chronic oral intake reference for Cr(VI) and is the baseline against which HMT&C Cr(VI) thresholds for ingested products are evaluated. For an HMT&C target of full daily intake at the RfD via a single product category, the implied per-kg product concentration depends on serving size and bodyweight; ratcheting decisions for Cr(VI) belong on certification pages, not here. The 0.27 (mg/kg-day)⁻¹ lifetime OSF is the cancer-risk anchor for low-dose dietary Cr(VI) exposure. The susceptible-population list (elevated stomach pH including all infants under 30 months) is directly material to threshold-setting for infant-targeted product categories.
- Courses: The assessment is a teachable example of (1) how EPA handles a chemical with mode-of-action divergence between oral and inhalation routes (the GI-tract first-pass reduction is the dominant mechanistic feature), (2) how PBPK modeling is layered onto rodent bioassay HEDs when species differences in detoxification capacity are large, and (3) how ADAFs are applied for mutagenic carcinogens.
- App: Cr(VI) reference values land on chromium-hexavalent; consumer translation should use the µg/kg-bw/day daily-intake framing rather than µg/L or µg/kg-food directly. The app’s drinking-water Cr(VI) exposure pathway needs the RfD for non-cancer risk and the OSF for lifetime cancer risk.
- Microbiome: Not directly addressed in this assessment; the CFTR-related susceptibility note is a host-genetics observation rather than a microbiome interaction.
Provenance notes
License us-government-work. The PDF was retrieved as EPA/635/R-24/164Fa (August 2024) and resides locally at raw/Manual Fetch Kimi / EPA:635:R-24:164Fa www.epa.gov:iris IRIS Toxicological Review of Hexavalent Chromium [Cr(VI)] CASRN 18540-29-9.pdf (SHA-256 b21931b404750dd9efcd6cabb33c2232ed4533152fb6b44d6b0a1c506fbbafc0). The canonical access channel is the EPA IRIS website (epa.gov/iris); the assessment-specific landing page typically resolves through the IRIS Substance Quick View by CASRN 18540-29-9. The August 2024 assessment supersedes the 1998 IRIS Cr(VI) assessment for both oral and inhalation reference-value derivation. Supplemental Information (Appendices A through G), including the full systematic review protocol, dose-response modeling appendices, and public comment responses, is published as a separate Volume 2 and is not included in the raw PDF processed here.
This source warrants a dedicated regulation page (suggested regulations/epa-iris-chromium-hexavalent-rfd-osf) capturing the chronic oral RfD (9 × 10⁻⁴ mg/kg-day), chronic inhalation RfC (3 × 10⁻⁵ mg/m³), lifetime oral slope factor (0.27 per mg/kg-day with ADAFs), and lifetime inhalation unit risk (1.8 × 10⁻² per µg/m³ with ADAFs). That page is not created in this ingest cycle; the source values are captured here for routing.
Wiki pages updated on ingest
Page history
The five most recent substantive edits to this page. The full version history lives in git; when DOI minting comes online (see schema docs), each entry below will also link to a version-pinned DataCite DOI.
| Commit | Date | Description |
|---|---|---|
| 12d44c4 | 2026-05-29 | audit: eaglessmith2016-freshwater-fish-mercury-western-us-canada [revised] |