Differences between humans and rats in chloroform-induced effects on the olfactory epithelium ?
N. Hund1, B. Brinkmann1, R. Bartsch1, G. Schriever-Schwemmer1, G. Jahnke1, A. Hartwig1
1 Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission), Karlsruhe Institute ofTechnology (KIT), Institute of Applied Biosciences, Department of Food Chemistry and Toxicology, Karlsruhe, Germany

Introduction

Oxidative Metabolism

The Permanent Senate Commission for the Investigation ofHealth Hazards of Chemical Compounds in the Work Area(MAK Commission) proposes maximum workplaceconcentrations (MAK values) for chemicals in order to provide
comprehensive information for workplace safety professionals
and researchers and to give scientific policy advice. Members
and contributors of the MAK Commission come from different
scientific fields like toxicology, epidemiology, occupationalmedicine, veterinary medicine, biochemistry, molecular biology,
analytical chemistry, dermatology, pathology and statistics.
Recently, the MAK Commission re-evaluated the hazard ofchloroform at the workplace.
Chloroform was used as an inhalation narcotic until the end of
the 19th century before its harmful effects on the liver andkidneys were recognized. Nowadays, it is used as a solvent andin chemical synthesis. Furthermore, chloroform is contained incleaning and disinfecting agents and large amounts areproduced as by-products in the chlorination of drinking water.

3Chloroform-H2O+O2

Cytochrome P450 2E1

Glutathione
Conjugation
Carbonic acid

HOCCl3
GSH

Cysteine
H2O
2 HCl + CO2-HClO CH2Cl2
Phosgene

R-OH
R-SH
R-NH2

Most relevant
toxic pathway

RCCl2OH

Acylation ofproteins and enyzmes

Objectives• Chloroform affects the central nervous system, liver and kidneys after oral and inhalation exposure• In 1999: a NOAEC (no observed adverse effect concentration) of 5 ml/m3 in a 13-week inhalation study was determined based on increased cell proliferation in the kidneys and liver of rats and mice
 A MAK value of 0.5 ml/m3 was established• New: 2-year inhalation study in rats and mice  nasal lesions play a major role in chloroform-induced toxicity• However: differences in anatomy, physiology and air flow dynamics in the nasal cavity between humans and rodents• Question: Are rodents more sensitive for effects in the olfactory epithelium (OE)?

Methods
A comprehensive literature search on the toxicity of chloroform was performed. Reviews by other regulatory bodies and original
studies on inhalation toxicity and metabolism were discussed and evaluated within an expert committee of the MAK Commission.

Results
In the new 2-year inhalation study, thickening of the bone in the nasal cavity and respiratory metaplasia of the OE were observed at10 ml chloroform/m³ in rats. The pathomechanism of thickening of the bone is due to a degeneration of the Bowman’s glands,
which are located in the OE. However, there are differences in anatomy, physiology, and air flow dynamics between humans andrats:

breathingobligate nose
average percentage of OE
50 %air flow over OE
15 %enzyme activity of CYP2E1 in OEa

nasal and oral
3%
7%
no• Substances that cause effects in the Bowman’s glands of the OE are therefore particularly toxic for rodents• As CYP2E1 is the key enzyme that metabolizes chloroform to the toxic phosgene, it is assumed that rodents are more sensitive
than humans
a: Green T, Lee R, Toghill A, Meadowcroft S, Lund V, Foster J (2001) The toxicity of styrene to the nasal epithelium of mice and rats: studies on the mode of action and relevance to humans. Chem Biol Interact 137(2): 185–202

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MAK value derivation and conclusion

LOAEC: 10 ml chloroform/m³ due to effects on the OE in rats
Since humans are less sensitive than rodents, no factor is needed for the extrapolation of the animal data to humans
MAK value derived from effects in the nose would correspond to 1 ml/m3
Kidney and liver effects correspond to 0.5 ml/m³

The present MAK value of 0.5 ml/m³ thus protects also against effects in the nose
Further information: www. dfg.de/en/mak

KIT – University of the State of Baden-Wuerttemberg andNational Research Center of the Helmholtz AssociationPoster download: