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Formate is a moderate respiratory chain inhibitor (Ki approx. 6 mM) which may be associated with ocular damage seen when elevated formate levels persist (approx. blod levels 7mM, min. 24 hours). The ocular damage is associated with low hepatic folate levels and, hence, slow  formate metabolism. It was demonstrated to occur in vitro, and in vivo in non-human primates (monkeys) and in pretreated rats receiving formate.

Additional information

Experimental animals metabolise formate more rapidly than humans and non-human primates, primarily due to higher hepatic folate levels. As a consequence, formate does not accumulate. It may, however, accumulate in humans and monkeys. Therefore, these species differences obscure potential adverse formate effects in experimental animals but may occur in humans.

After methanol poisoning, irreversible ocular toxicity (retina, optical nerve) is seen in humans but not in rodents, and it is attributable to folate. This was confirmed by experiments in vitro and in vivo where functional and morphological changes of the retina and the optical nerve were demonstrated with formic acid and sodium formate (Emmrich, 2002). Monkeys developed ocular lesions when plasma formate levels were increased over an extended period of time (>550 mg/L [approx. 12 mM], > 24 hours) by means of i.v. infusion of sodium formate (Martin-Amat, 1978). Additionally, a rat model was developed to demonstrate ocular toxicity in rats. Pretreatment with N2O significantly reduces the folate level in rats, and functional and morphological lesions are then obtained in rats receiving methanol or sodium formate (Eells, 2000). Formate-induced retinal toxicity in pretreated, methanol-intoxicated rats was recently demonstrated to occur at 2.6 mM formate after 24 hours (Seme, 1999). According to Hanzlik, blood formate must exceed 7 mM (i.e. 315 mg/L) for at least 24 hours to produce irreversible ocular damage to occur in humans.

Folate is a moderate inhibitor (Kiapprox 6 mM) of cytochrome c oxydase, i.e. it impairs respiratory chain and proper ATP supply of the affected cells, it favours generation of lactic acid and, hence, acidosis on a cellular level (Nicholls, 1976; Erecinska and Wilson, 1980). This pattern was seen in photoreceptor cells and optical nerve cells after in vitro or in vivo formate treatment. However, the exact mechanism of ocular toxicity is still not fully understood. It should be noted that folate treatment in vivo does not lead to acidosis, in contrast to methanol poisoning.