PERMITTED DAILY EXPOSURE (PDE)

PERMITTED DAILY EXPOSURE (PDE) or ACCEPTANCE DAILY EXPOSURE

Introduction

During the manufacture of medicinal products accidental cross contamination can result from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances, other starting materials, and other products being processed concurrently, as well as from residues on equipment, and from operators’ clothing. Due to the perceived risk, certain classes of medicinal product have previously been required to be manufactured in dedicated or segregated self contained facilities including, “certain antibiotics, certain hormones, certain cytotoxics and certain highly active drugs”. Until now no official guidance is available in order to assist manufacturers to differentiate between individual products within these specified classes.

METHODS FOR ESTABLISHING EXPOSURE LIMITS

The Gaylor-Kodell method of risk assessment (Gaylor, D. W. and Kodell, R. L.: Linear Interpolation algorithm for low dose assessment of toxic substance. J Environ. Pathology, 4, 305, 1980) is appropriate for Class 1 carcinogenic solvents. Only in cases where reliable carcinogenicity data are available should extrapolation by the use of mathematical models be applied to setting exposure limits. Exposure limits for Class 1 solvents could be determined with the use of a large safety factor (i.e., 10,000 to 100,000) with respect to the no-observed-effect level (NOEL). Detection and quantitation of these solvents should be by state-of-the-art analytical techniques.

Acceptable exposure levels in this guideline for Class 2 solvents were established by calculation of PDE values according to the procedures for setting exposure limits in pharmaceuticals (Pharmacopeial Forum, Nov-Dec 1989), and the method adopted by IPCS for Assessing Human Health Risk of Chemicals (Environmental Health Criteria 170, WHO, 1994). These methods are similar to those used by the USEPA (IRIS) and the USFDA (Red Book) and others. The method is outlined here to give a better understanding of the origin of the PDE values. It is not necessary to perform these calculations in order to use the PDE values tabulated in Section 4 of this document. PDE is derived from the no-observed-effect level (NOEL), or the lowest-observed effect level (LOEL) in the most relevant animal study as follows:

PDE =        NOEL x Weight Adjustment

                        F1 x F2 x F3 x F4 x F5

The PDE is derived preferably from a NOEL. If no NOEL is obtained, the LOEL may be used. Modifying factors proposed here, for relating the data to humans, are the same kind of "uncertainty factors" used in Environmental Health Criteria (Environmental Health Criteria 170, World Health Organization, Geneva, 1994), and "modifying factors" or "safety factors" in Pharmacopeial Forum. The assumption of 100% systemic exposure is used in all calculations regardless of route of administration. The modifying factors are as follows:

F1 = A factor to account for extrapolation between species

F1 = 5 for extrapolation from rats to humans

F1 = 12 for extrapolation from mice to humans

F1 = 2 for extrapolation from dogs to humans

F1 = 2.5 for extrapolation from rabbits to humans

F1 = 3 for extrapolation from monkeys to humans

F1 = 10 for extrapolation from other animals to humans

 F1 takes into account the comparative surface area:body weight ratios for the species concerned and for man. Surface area (S) is calculated as:

S = kM0.67

in which M = body mass, and the constant k has been taken to be 10. The body weights used in the equation are those shown below in Table A.

F2 = A factor of 10 to account for variability between individuals

A factor of 10 is generally given for all organic solvents, and 10 is used consistently in ICH guideline.

F3 = A variable factor to account for toxicity studies of short-term exposure

F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for cats, dogs and monkeys).

 F3 = 1 for reproductive studies in which the whole period of organogenesis is covered.

 F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents.

 F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents.

F3 = 10 for studies of a shorter duration.

 In all cases, the higher factor has been used for study durations between the time points, e.g., a factor of 2 for a 9-month rodent study.

F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic carcinogenicity, neurotoxicity or teratogenicity. In studies of reproductive toxicity, the following factors are used:

 F4 = 1 for fetal toxicity associated with maternal toxicity

F4 = 5 for fetal toxicity without maternal toxicity

F4 = 5 for a teratogenic effect with maternal toxicity

F4 = 10 for a teratogenic effect without maternal toxicity

F5 = A variable factor that may be applied if the no-effect level was not established

When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.

The weight adjustment assumes an arbitrary adult human body weight for either sex of 50 kg. This relatively low weight provides an additional safety factor against the standard weights of 60 kg or 70 kg that are often used in this type of calculation. It is recognized that some adult patients weigh less than 50 kg; these patients are considered to be accommodated by the built-in safety factors used to determine a PDE. If the solvent was present in a formulation specifically intended for pediatric use, an adjustment for a lower body weight would be appropriate.

 As an example of the application of this equation, consider a toxicity study of acetonitrile in mice that is summarized in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997, page S24. The NOEL is calculated to be 50.7 mg kg-1 day-1. The PDE for acetonitrile in this study is calculated as follows:

PDE =        50.7 mg kg^-1 day ^-1 x 50 kg                =   4.22 mg day ^-1

                        12 x 10 x 5 x 1 x 1

In this example,

F1 = 12 to account for the extrapolation from mice to humans

F2 = 10 to account for differences between individual humans

F3 = 5 because the duration of the study was only 13 weeks

F4 = 1 because no severe toxicity was encountered

F5 = 1 because the no effect level was determined

Table A Values used in the calculations in this document.

rat body weight 425 g                                               mouse respiratory volume 43 L/day

pregnant rat body weight 330 g                                 rabbit respiratory volume 1440 L/day

mouse body weight 8 g                                                   guinea pig respiratory volume 430 L/day

pregnant mouse body weight 30 g                                 human respiratory volume 28,800 L/day

guinea pig body weight500 g                                 dog respiratory volume 9,000 L/day

Rhesus monkey body weight 2.5 kg                             monkey respiratory volume 1,150 L/day

rabbit body weight (pregnant or not) 4 kg                       mouse water consumption 5 mL/day

beagle dog body weight 11.5 kg                                      rat water consumption 30 mL/day

rat respiratory volume 290 L/day                                     rat food consumption 30 g/day

The equation for an ideal gas, PV = nRT, is used to convert concentrations of gases used in inhalation studies from units of ppm to units of mg/L or mg/m3. Consider as an example the rat reproductive toxicity study by inhalation of carbon tetrachloride (molecular weight 153.84) is summarized in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997, page S9.

n =  P =           300 x 10^-6atm x 153840 mg mol^-1       =       46.15 mg        =   1.89 mg / L

V   RT               0.082  Latm K^-1mol^-1    x  298   K              24045  L

The relationship 1000 L = 1 m³ is used to convert to mg/ m³.