11.3 Inhalation Dosimetry: Human Equivalent Concentrations (HEC) & Regional Gas Dose Ratios (RGDR)
Key Takeaways
- EPA 1994 RfC methodology sorts gases into Category 1 (highly soluble and/or reactive, portal-of-entry), Category 3 (poorly soluble, remote/systemic), and Category 2 (mixed, using the Category 1 or 3 math that matches the observed effect).
- For portal-of-entry gases, RGDR is the animal-to-human ratio of minute ventilation divided by regional airway surface area; for Category 3 extrarespiratory effects, the dosimetric ratio is the blood:air partition pair, capped at 1 when the animal partition exceeds the human.
- Human equivalent concentration HEC = duration-adjusted point of departure × RGDR (gases) or × RDDR (particles).
- Duration adjustment to continuous exposure multiplies by (hours per day / 24) × (days per week / 7); an occupational 8 h/5 d human concentration scales by (8/24) × (5/7).
- Extra-thoracic and tracheobronchial regions are the usual Category 1 irritant targets; the alveolar/pulmonary region is the gas-exchange surface for poorly soluble gases and for respirable particles.
Why inhalation is not a gavage milligram-per-kilogram
An oral RfD is a dose. An inhalation reference concentration (RfC) is a concentration in air intended to be without appreciable risk over a lifetime of continuous exposure. You cannot honestly compare a 6-hour nose-only rat chamber concentration with an 8-hour workplace TWA or with a 24-hour residential indoor concentration until you have done duration adjustment and interspecies dosimetry. Handbook III.C.1 G sits with dose–response, but the mechanics are exposure dosimetry, which is why this chapter teaches them here. Independent OpenExamPrep coverage follows EPA’s 1994 Methods for Derivation of Inhalation Reference Concentrations (the RfC methodology) at a conceptual level: gas categories, regional gas dose ratio (RGDR), particle regional deposited dose ratio (RDDR), human equivalent concentration (HEC), and the calendar conversion from occupational or animal schedules to continuous exposure. It is not an ABT product and does not claim official approval, review, or partnership with ABT or EPA.
Superfund RAGS Part F made the same point for site risk: keep inhalation as mg/m³ (an exposure concentration averaged with the same EF/ED/AT logic as oral doses) and compare it with an RfC or inhalation unit risk. Do not convert air to mg/kg-day with 20 m³/day merely to reuse an oral slope factor that was never an inhalation toxicity value.
Category 1, 2, and 3 gases
EPA sorts gases by solubility and reactivity because those properties decide where the molecules are absorbed and therefore which surface area and which physiologic ratio belong in the math.
Category 1. Highly water-soluble and/or rapidly, irreversibly reactive in the airway (teaching examples: chlorine, hydrogen fluoride, acrolein, formaldehyde as an upper-airway reactive gas). They do not accumulate much in blood. Effects are usually portal-of-entry in the respiratory tract, often the extra-thoracic (ET) region (nose, larynx) in nose-breathing rodents. Dosimetry uses RGDR from minute ventilation (VE) and the surface area of the affected region.
Category 3. Relatively water-insoluble and unreactive in the tract (many systemic solvents). They reach the alveolar (pulmonary) region, enter blood, and cause remote (extrarespiratory) effects. The default dosimetric adjustment is the ratio of blood:air partition coefficients (animal/human). If the animal partition exceeds the human partition, EPA caps the ratio at 1—the human is not assumed to achieve a higher arterial concentration than the animal on that basis.
Category 2. Intermediate solubility/reactivity; absorption along the airways and some uptake into blood. Effects may be portal-of-entry, remote, or both. In practice, assessors apply the Category 1 RGDR to a respiratory-tract endpoint and the Category 3 partition ratio to a remote endpoint rather than inventing a fourth equation. Category 2 is a warning that both stories may be in the file, not a free pass to skip dosimetry.
| Category | Physicochemistry | Typical site of effect | Default dosimetric ratio |
|---|---|---|---|
| 1 | High water solubility and/or rapid reactivity | Portal of entry (ET, sometimes TB) | RGDR = (VE/SA)animal / (VE/SA)human for that region |
| 2 | Moderate solubility/reactivity | Portal of entry and/or remote | Use the Category 1 or 3 form that matches the endpoint |
| 3 | Low solubility, low reactivity | Remote / extrarespiratory (systemic) | (Hb/g)animal / (Hb/g)human, not greater than 1 |
Particles are not gases. Regional deposition is an RDDR: the ratio of deposited dose per regional surface area (or per body weight, depending on the endpoint) between animal and human, using deposition fraction, ventilation, and regional surface. Historical Agency practice used RDDR software; conceptually you still need MMAD, breathing mode, and the region that was injured (ET, tracheobronchial, pulmonary). Coarse MMAD plus a pulmonary endpoint is a mismatch.
RGDR, default physiology, and HEC
For a Category 1 extra-thoracic effect, EPA 1994 Equation 4-18 is:
RGDR_ET = (VE / SA_ET)animal / (VE / SA_ET)human
Default teaching physiology from that methodology: rat VE 0.14 L/min and ET surface 15 cm²; human VE 13.8 L/min (the 20 m³/day default expressed as a minute rate) and ET surface 200 cm².
Compute: VE/SA rat = 0.14 / 15 = 0.00933 L/min per cm².
Human SA/VE = 200 / 13.8 = 14.49 cm² per (L/min).
RGDR_ET = 0.00933 × 14.49 = 0.135, which Agency examples often round to 0.14. The ratio is less than 1: per unit of inhaled concentration, the rat’s small ET surface sees a higher local dose than the human, so the human equivalent concentration is lower than the rat chamber concentration after this adjustment.
HEC = POD_ADJ × RGDR (or × RDDR for particles). The point of departure is first converted to a continuous concentration (POD_ADJ), then multiplied by the dosimetric ratio. Skipping either step is the usual examination error.
Minute ventilation (VE) is the volume moved in and out per minute (tidal volume × frequency). Alveolar ventilation (VA) is VE minus dead-space ventilation—the portion that actually participates in gas exchange. Portal-of-entry Category 1 math uses VE and regional airway surface area. Systemic Category 3 uptake is a blood:air and ventilation–perfusion story in which alveolar exchange, not the nasal surface, is the relevant absorber. Using ET surface area for a liver lesion from an insoluble solvent is the wrong category.
Duration adjustment (animal or occupational → continuous)
RfCs assume continuous exposure. A 6-hour, 5-day animal study, or an 8-hour, 5-day workplace, is not continuous. The linear default is:
C_ADJ = C × (hours per day / 24) × (days per week / 7)
Animal example. A NOAEL of 25 mg/m³, 6 h/day, 5 days/week:
6/24 = 0.25, so 25 × 0.25 = 6.25 mg/m³.
5/7 ≈ 0.714, and 6.25 × 5/7 = 31.25 / 7 = 4.464 mg/m³, reported as 4.46 mg/m³.
Exactly: 25 × (6/24) × (5/7) = 25 × (5/28) = 125/28 = 4.464 mg/m³.
If a hypothetical portal-of-entry RGDR = 0.50 is then applied, HEC = 4.46 × 0.50 = 2.23 mg/m³. (The 0.135 ET default above would instead give 4.46 × 0.135 ≈ 0.60 mg/m³.) The RfC still has uncertainty factors to apply after the HEC; HEC is not the RfC.
Occupational human example. A workplace TWA of 10 mg/m³ for 8 h/day, 5 days/week, already in humans so no interspecies RGDR:
(8/24) × (5/7) = 40/168 = 5/21 ≈ 0.238.
10 × 5/21 = 50/21 = 2.38 mg/m³ continuous-equivalent concentration. That number, not 10 mg/m³, is what you compare conceptually with a continuous RfC before any additional workplace/community differences in activity or particle size are discussed.
Some reactive Category 1 gases have concentration-dependent uptake that makes this linear hours/24 conversion crude; the examination still expects you to know the default product and when a PBPK or CFD model would replace it.
Scenario
A rat nose-only study of a highly soluble irritant reports a 6 h/5 d NOAEL of 25 mg/m³ for nasal epithelial lesions and no liver findings. The correct path is Category 1, duration-adjust to 4.46 mg/m³, apply an ET RGDR (about 0.14 with EPA 1994 defaults, not 1.0), and call that product the HEC. Using a Category 3 partition ratio of 1 because “the chemical is a gas,” or multiplying 25 mg/m³ by RGDR without the 6/24 and 5/7 steps, overstates the human equivalent. A second file is a poorly soluble solvent with hepatocellular lesions and a quiet nose: Category 3, extrarespiratory partition ratio (capped at 1), pulmonary/alveolar uptake, not an ET surface-area RGDR. A third file is an occupational cohort already in humans: duration-adjust 8/24 × 5/7, and do not apply a rat/human RGDR on top.
Traps
- Treating every gas as Category 3 because systemic toxicity is more familiar.
- Applying RGDR to the unadjusted 6-hour concentration, or duration-adjusting twice.
- Using ET surface area for an extrarespiratory liver endpoint, or a blood:air ratio for a chlorine-type nasal lesion.
- Converting RfC-basis air concentrations into mg/kg-day with 20 m³/day and 70 kg so they can sit beside an oral RfD.
- Setting occupational 8 h/5 d equal to residential 24 h/7 d without the 5/21 factor.
Chlorine produces nasal lesions in a nose-only rat study and does not accumulate in blood. A second chemical is a poorly soluble solvent that produces hepatocellular injury with a quiet nose. Which category assignment matches EPA 1994 RfC methodology?
A 6 h/day, 5 day/week animal NOAEL is 25 mg/m³. What is the duration-adjusted continuous POD_ADJ using (hours/24)×(days/7)?
After duration adjustment, a portal-of-entry POD_ADJ is 4.46 mg/m³ and the regional gas dose ratio is 0.50. What is the HEC, and what would an occupational 10 mg/m³ 8 h/5 d human TWA become as a continuous concentration?