Institutionen för molekylär medicin och kirurgi / Department of Molecular Medicine and Surgery
Abstract
Hydrofluorocarbons (HFCs) and hydrochlorofluorocarbons (HCFCs) have
replaced the chlorofluorocarbons (CFCs) in refrigeration installations
and air-conditioning applications. As substitution progressed, some
refrigeration mechanics experienced symptoms of inflammation. The new
refrigerants were well studied in animals, but data on toxicology and
toxicokinetics in humans were scarce. The aim of this thesis was to study
human toxicokinetics and effects of HFC-134a and HFC-143a. Moreover,
autoimmune responses due to exposure to halogenated hydrocarbons used as
refrigerants were investigated and a case of myocardial infarction was
discussed.
Toxicokinetics and Effects (Study I and II): Ten male volunteers were
exposed to 500 ppm HFC-134a and/or HFC-143a in an exposure chamber (2 h,
workload of 50 W). Blood, exhaled air, and urine were collected up to 19
h post-exposure and analysed for HFC with gas chromatography. The
experimental data was described by a physiologically-based toxicokinetic
(PBTK) model. Markers of inflammation (C‑reactive protein, serum amyloid
A protein, D-dimer, fibrinogen) and uric acid were analysed in plasma
collected before and 21 h post-exposure. The volunteers rated symptoms
related to irritation and CNS-symptoms on a visual analogue scale before,
during and after exposure.
The increase in blood upon exposure to HFC was fast, and apparent
steady-states (9.4 µM for HFC-134a, 4.8 µM for HFC143a) were reached
within minutes. The post-exposure decrease in blood was fast as well and
parallel to that of exhaled air. The urinary excretion of HFC‑134a and
HFC‑143a was less than 0.002% of the inhaled amount with half-times of 58
and 53 min. The experimental data fitted well within a PBTK framework,
and the relative respiratory uptake was estimated to 3.7 % for HFC‑134a
and 1.6% for HFC-143a. No effect due to exposure was seen on symptom
ratings or in the electrocardiographic recordings. Fibrinogen plasma
concentration had increased after exposure to both HFCs, whereas none of
the other inflammatory markers or uric acid had increased significantly.
Further studies are needed to confirm or reject this finding.
Autoimmune Response (Study III): Serum samples from 44 Swedish men,
occupationally exposed to refrigerants, were screened for antibodies
against CYP2E1 with enzyme-linked immunosorbent assay. The men
participating in the study were selected from a cohort of 280
refrigeration mechanics. One group comprised 30 men with asthma, joint or
influenza-like symptoms and another exposed group comprised 14 men with
no such symptoms. Unexposed, healthy subjects from Sweden (n=35) and
Italy (n=26) constituted control groups.No increase in CYP2E1 antibody
titer was seen among occupationally exposed persons compared to unexposed
controls. Neither were there any differences between exposed, symptomatic
subjects and healthy exposed or unexposed ones. Further, no relation
between antibody titer and severity of symptoms, smoking, inhaled
anesthetics, age, or year in occupation was detected.
Case Report (Study IV): A case of myocardial infarction was reported.
Possible associations between welding, exposure to decomposed HCFC-22,
respiratory symptoms and the myocardial infarction were discussed.
In conclusion, the respiratory uptake of HFC-134a and HFC-143a is low and
the post-exposure decrease in blood and exhaled air is fast. There may be
an inflammatory response at 500 ppm exposure level (i.e. at the Swedish
occupational exposure limit, 8‑h time-weighted average), but further
studies are needed to confirm this response. Exposure to halogenated
hydrocarbons could not be associated to CYP2E1-related autoimmunity
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