The pattern of mutations in the oncogenes from liver tumours that occurred spontaneously differed from that which occurred in some furfural-treated animals: The activated ras genes were H- ras in 15 of 17 spontaneous tumours, with one raf and one unknown oncogene; activating point mutations occurred at codon 61 in six tumours, codon 13 in two tumours, and codon 117 in one tumour.
Rats that had been treated with N-2-fluorenylacetamide developed multiple hyperplastic nodules which stained for alpha-fetoprotein, and this response was markedly potentiated in the rats previously treated with furfural.
Biochemical changes in the lungs and livers of animals exposed to furfural indicate that ring oxidation may be catalysed by a cytochrome P450b isoenzyme, yielding an intermediate which subsequently conjugates with glutathione (Gupta et al., 1991; Mishra et al., 1991).
Humans As in laboratory animals, the predominant pathway for detoxification of furfural in humans is oxidation of the aldehyde to yield furoic acid, which either conjugates with amino acids or condenses with acetyl CoA to produce furanacrylic acid.
The absorption (83-90%), tissue distribution (primarily liver and kidney), relative amounts of metabolites (urine, 76-105%; faeces, 1-7%; breath, 4-7%; tissues, 1%), and pattern of excretion in mice and rats were linear over the range of doses investigated (0.1-200 mg/kg bw of furfural) (Nomeir et al., 1992; Parkash & Caldwell, 1994).
After inhalation or dermal absorption, furfural is efficiently and rapidly absorbed ithrough the lungs and skin, with 20-30% of the amount absorbed by the lungs (Flek & Sedivec, 1978).
Essentially all of the absorbed furfural could be accounted for: 97% (range, 93-100%) was oxidized to 2-furoic acid and excreted as the glycine conjugate, 0.5-5% was excreted as furanacrylic acid, and less than 1% was exhaled unchanged.
The reactivity of the aldehyde function of aldehydes of low molecular mass, like furfural, suggests that such compounds are not absorbed intact at doses that do not saturate the oxidation or condensation reactions associated with the aldehyde function in digestive fluids.
2.2 Toxicological studies 2.2.1 Acute toxicity On the basis of the oral LD50 values in various species (Table 1), furfural is acutely toxic at lower doses in rats than in mice.
Wistar/Slc rats given a single dose of 50 mg/kg bw furfural by gavage had sporadic eosinophilic degeneration of hepatic cells with nuclear pyknosis and eosinophilic necrosis and increased hepatocyte mitosis.
Acute toxicity of furfural Species Route LD50 (mg/kg bw) Reference or LC50 (mg/m3) Rat Oral 127 Jenner et al.
(1983) 2.2.2 Short-term studies of toxicity Rats In rats receiving 0.05, 2.5, or 25 mg/kg bw per day furfural for 35 days, no hepatic impairment was seen (Kuznetsov, 1966).
When male rats were injected intraperitoneally with furfural in increasing doses from 29 to 58 mg/kg bw for 30 days, damage and increased intracellular catabolic processes were seen in liver and kidney cells (Kaminska, 1977).
In a 16-day study, groups of five male and five female Fischer 344/N rats were given furfural at doses of 0, 15, 30, 60, 120, or 240 mg/kg bw per day in corn oil by gavage, five days per week for a total of 12 doses.
Furfural is metabolized primarily by oxidation of the aldehyde function in rats (Paul et al., 1949; Rice, 1972; Nomeir et al., 1992; Parkash & Caldwell, 1994) and mice (Parkash & Caldwell, 1994).