Document ID: EPA-HQ-OPP-2005-0123-0288
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-02T04:00Z

Appendix B

Methodologies for Inhalation Risk Calculations

and

Human Equivalent Concentration Arrays

METHODOLOGIES FOR INHALATION RISK CALCULATIONS

In evaluating the risks that a compound may pose to human health after
exposure via the inhalation route, different methodologies have been
historically used by the USEPA and CDPR.  

The Agency’s approach to calculating risks due to inhalation exposure
is based on the guidance methodology developed by the Office of Research
and Development (ORD) for the derivation of inhalation reference
concentrations (RfCs) and human equivalent concentrations (HECs) for use
in margin of exposure (MOE) calculations (RfC methodology).   An example
of CDPR’s methodology, and the species-specific parameters used in
this approach can be found in the CDPR methyl bromide risk assessment,
Appendix G (   HYPERLINK http://www.cdpr.ca.gov
www.cdpr.ca.gov/docs/dprdocs/methbrom/append_g.pdf ).  As OPP
understands the importance to harmonize, to the extent possible, with
other regulatory agencies, this risk assessment will present HECs
derived using both methodologies.

The RfC methodology applies a dosimetric adjustment that takes into
consideration not only the differences in ventilation rate (MV) but also
the physicochemical properties of the inhaled compound, the type of
toxicity observed (e.g. systemic vs. port of entry) and the 
pharmacokinetic (PK) but not pharmacodynamic (PD) differences between
animals and humans.  Based on the RfC guidance (1994), the methodology
for RfCs derivation is an estimate of the quantitative dose-response
assessment of chronic non-cancer toxicity for individual inhaled
chemicals and includes dosimetric adjustment to account for the
species-specific relationships of exposure concentration to
deposited/delivered dose. This adjustment is influenced by the
physicochemical properties of the inhaled compound as well as the type
of toxicity observed (e.g. systemic vs. port of entry), and takes into
consideration the PK differences between animals and humans.  Though the
RfC methodology was developed to estimate toxicity of inhaled chemicals
over a lifetime, it can be used for other inhalation exposures (e.g.
acute and short-term exposures) since the dosimetric adjustment
incorporates mechanistic determinants of disposition that can be applied
to shorter duration of exposures provided the assumptions underlying the
methodology are still valid.  These assumptions, in turn, vary depending
on the type of toxicity observed and will be discussed later on in this
document.  Thus the derivation of a HEC for inhaled gases is described
by the following equation:

   ADVANCE \u 13 

Where:

PODstudy: Point of departure identified in the critical toxicology study

Danimal exposure: Duration of animal exposure (hrs/day; days/wk)

Danticipated exposure: Anticipated human duration of exposure (hrs/day;
days/wk)

RGDR: Regional Gas Dose Ratio

For gases eliciting both port of entry and systemic effects,
calculations to estimate  the inhalation risk to humans are dependent on
the regional gas dose ratio (RGDR).  In the case of systemic effects,
the RGDR is defined as the ratio of the blood:gas partition coefficient
of the chemical for the test species to humans (Hb/g animal/Hb/g human).
 When this ratio is unknown or when the Hb/g animal > Hb/g human a
default value of  1.0 is used as the RGDR.  This default is based on the
observation that for chemicals where partition coefficient data are
available in both rats and humans the RGDR value has usually been
comparable or slightly higher than 1.  Thus, the use of an RGDR of 1
results in a protective calculation of the inhalation risk.   Some of
the key assumptions fundamental to the use of the RfC methodology to
derive a HEC based on systemic effects include:

1) all the concentrations of inhaled gas within the animal’s body are
periodic with respect to time (i.e. periodic steady state - the
concentration vs time profile is the same for every week).  Periodicity
must be attained for at least 90% of the exposure.

2) in the respiratory tract, the air, tissue, capillary blood
concentration are in equilibrium with respect to each other.

3)systemically, the blood and tissue concentrations are in equilibrium
with respect to each other.

In the case of MeBr, the physicochemical properties and metabolism data
for the compound indicate that these conditions (i.e. periodicity and
equilibrium between different compartments) will be achieved in a very
short period of time.  Under these conditions, therefore, the use of the
RfC methodology to estimate acute inhalation risk is appropriate.    

When the critical toxic effect in a study occurs in the respiratory
tract (i.e port of entry effects), the RGDR is not related to the
blood:gas partition coefficient of the compound but rather the ratio of
the minute volume (MV) to the surface area (SA) of the affected region. 
In these instances, attaining periodicity or equilibrium between the
compartments is not critical (since the effect is a function of the
direct interaction between the inhaled compound and the affected region
in the respiratory tract) and the RGDR may be calculated using the
following equation:

   ADVANCE \u 19 

Where:

	MV animal: Minute volume for the test species (varies depending on body
weight)

SA animal: Surface area of the affected region in animals

MV human: Minute volume for humans (default value is 13.8 l/min)

SA human: Surface area of the affected region in humans

The MV animal is calculated using the allometric scaling provided in
USEPA (1988a).  The equation for calculation of the MV animal is:

lnMV animal = b0 + b1ln(BW)

Where:

ln MV animal : natural logarithm of the minute volume

b0 : species specific intercept used in the algorithm to calculate
minute volumes based on body weight

b1: species specific coefficient used in the algorithm to calculate
minute volumes based on body weight

ln BW: natural logarithm of the body weight (expressed in kg)

The values for the species-specific parameters used to calculate the MV
animal based on body weight and the values for the surface areas of
various regions of the respiratory tract (extrathoracic, thoracic, and
pulmonary) are provided in the EPA document “Methods for Derivation of
Inhalation Reference Concentrations and Application of Inhalation
Dosimetry” (1994).

The magnitude of the UFs applied is dependent on the methodology used to
calculate risk.  When using the methodology developed by CDPR, a 100X UF
is applied (10X for interspecies extrapolation and 10X for intraspecies
variation).  In contrast, the RfC methodology takes into consideration
the PK differences but not the PD differences.  Consequently, the UF for
interspecies extrapolation may be reduced to 3X (to account for the PD
differences) while the UF for intraspecies variation is retained at 10X.
 Thus, the UF when using the RfC methodology is customarily 30X.

Hazard Assessment Array

HEC Array for Non-Occupational Risk Assessment§

Relevant Study	LOAEL (ppm)	NOAEL (ppm)	Da	Dh	Wa	Wh	RGDR	HEC (ppm)	 Inter
	Intra	UF

Acute Exposure – Soil Fumigation Scenario

ACN- Rat	Systemic	350	100	6	24	1	1	1	25	10	3	1

Dev Rat	Systemic	NA	NA	6	24	1	1	NA	NA	NA	NA	1

Dev Rabbit	Systemic	80	40	6	24	1	1	1	10	10	3	1

Acute Exposure - Greenhouse or Structural Fumigation Scenarios†

ACN- Rat	Systemic	350	100	6	6	1	1	1	100	10	3	1

Dev Rat	Systemic	NA	NA	6	6	1	1	NA	NA	NA	NA	1

Dev Rabbit†	Systemic	80	40	6	6	1	1	1	40	10	3	1

Short Term Exposure

ACN-Rat	Adult	350	100	6	24	1	1	1.00	25	10	3	1

Dev Rat	Maternal

Systemic	70	20	6	24	5	7	1	3.6	10	3	1

	Developmental	NA	70	6	24	5	7	1	13	10	3	1

Dev Rabbit

	Maternal Systemic	80	40	6	24	5	7	1	7.1	10	3	1

	Developmental	80	40	6	24	5	7	1	7.1	10	3	1

SCN-Rat	Systemic	140	70	6	24	5	7	1	13	10	3	1

90D Dog	Systemic	10	5	7	24	5	7	1	1.0	10	3	1

MultiGen Repro: Rat

	Maternal

Systemic	90	30	6	24	5	7	1	5.4	10	3	1

	Offspring

Systemic	30	3	6	24	5	7	1	0.54	10	3	1

DNT	Maternal

Systemic	NA	50	6	24	7	7	1	12.50	10	3	1

	Offspring

Systemic	25	5	6	24	7	7	1	1.25	10	3	1

Intermediate Term Exposure

SCN-Rat	Systemic	70	30	6	24	5	7	1	5.4	10	3	1

90D Dog	Systemic	10	5	7	24	5	7	1	1.0	10	3	1

MultiGen Repro: Rat	Maternal Systemic	90	30	6	24	5	7	1	5.4	10	3	1

	Offspring Systemic	30	3	6	24	5	7	1	0.54	10	3	1

DNT	Maternal

Systemic	NA	50	6	24	7	7	1	12.50	10	3	1

	Offspring

Systemic	25	5	6	24	7	7	1	1.25	10	3	1

Long Term Exposure

SCN-Rat	Systemic	70	30	6	24	5	7	1	5.4	10	3	1

90D Dog	Systemic	10	5	7	24	5	7	1	1.0	10	3	1

MultiGen Repro: Rat	Maternal Systemic	90	30	6	24	5	7	1	5.4	10	3	1

	Offspring Systemic	30	3	6	24	5	7	1	0.54	10	3	1

Chronic Rat	Local	3	NA	6	24	5	7	0.244	0.7320	10	3	3¶

Chronic Mouse	Systemic	100	33	6	24	5	7	1	5.9	10	3	1

§ Bolded studies used for endpoint selection.

¶ A 3X UF for LOAEL to NOAEL extrapolation is recommended due to the
minimal severity of the portal of entry effects noted at the lowest dose
tested.

† 6 hour HECs developed to assess 6 hour exposure from a greenhouse or
structural fumigation scenario.

HEC Array for Occupational Risk Assessment§

Relevant Study	LOAEL (ppm)	NOAEL (ppm)	Da	Dh	Wa	Wh	RGDR	HEC (ppm)	Inter
Intra 	UF

Acute Exposure

ACN-Rat	Systemic	350	100	6	8	1	1	1	75	3	10	1

Dev Rat	Systemic	NA	NA	6	8	1	1	NA	NA	NA	NA	NA

Dev Rabbit	Systemic	80	40	6	8	1	1	1	30	3	10	1

Short Term Exposure

ACN-Rat	Systemic	350	100	6	8	1	1	1	75	3	10	1

Devel Rat	Maternal Systemic	70	20	6	8	5	5	1	15	3	10	1

	Developmental	NA	70	6	8	5	5	1	53	3	10	1

Dev Rabbit	Maternal Systemic	80	40	6	8	5	5	1	30	3	10	1

	Developmental	80	40	6	8	5	5	1	30	3	10	1

SCN-Rat	Systemic	140	70	6	8	5	5	1	53	3	10	1

90D Dog	Systemic	10	5	7	8	5	5	1	4.4	3	10	1

DNT	Maternal

Systemic	NA	50	6	8	7	7	1	37.50	10	3	1

	Offspring

Systemic	25	5	6	8	7	7	1	3.75	10	3	1

Intermediate Term Exposure

SCN-Rat	Systemic	70	30	6	8	5	5	1	23	3	10	1

90D Dog	Systemic	10	5	7	8	5	5	1	4.4	3	10	1

MultiGen Repro: Rat	Maternal Systemic	90	30	6	8	5	5	1	23	3	10	1

	Offspring Systemic	30	3	6	8	5	5	1	2.3	3	10	1

Chronic Mouse	Systemic	100	33	6	8	5	5	1	25	3	10	1

DNT	Maternal

Systemic	NA	50	6	8	7	7	1	37.50	10	3	1

	Offspring

Systemic	25	5	6	8	7	7	1	3.75	10	3	1

Long Term Exposure

SCN-Rat	70	30	6	8	5	5	1	23	3	10	1

90D Dog	10	5	7	8	5	5	1	4.4	3	10	1

MultiGen Repro: Rat	Maternal	90	30	6	8	5	5	1	23	3	10	1

	Offspring Systemic	30	3	6	8	5	5	1	2.3	3	10	1

Chronic Rat	3	NA	6	8	5	5	0.244	0.549	3	10	3¶

Chronic Mouse	100	33	6	8	5	5	1	25	3	10	1

§ Bolded studies used for endpoint selection.

¶ A 3X UF for LOAEL to NOAEL extrapolation is recommended due to the
minimal severity of the portal of entry effects noted at the lowest dose
tested.

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Key for Array Table

LOAEL: Lowest observed adverse effect level

NOAEL: No observed adverse effect level

Da: Daily animal exposure (hrs/day)

Dh: Anticipated daily human exposure (hrs/day)

Wa: Weekly animal exposure (days/week)

Wh: Anticipated weekly human exposure (days/week)

RGDR: Regional Gas Dose Ratio

HEC: Human Equivalent Concentration

inter: interspecies extrapolation uncertainty factor

intra: intraspecies variation uncertainty factor

UF: Other uncertainty factor(s)