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General aspects / read-across

Diarsenic trioxide is soluble in water (17.8 g/L). Upon dissolution in water, it reacts acidically to trivalent arsenite ions which are not subject to any relevant degree of oxidation for up to 72 hours, which is why it is assumed that read-across from toxicological data on inorganic arsenites to diarsenic trioxide is justified without restrictions.However, it is also known that in the human body, inorganic arsenic compounds are converted apart from As(III) also to As(V). Upon becoming systemically available, As(V) is rapidly partly converted to As(III). As(III) species are considered to be somewhat more toxic and bioactive than As(V) species.

 

Absorption

Oral:

Each of the forms of arsenic has different physicochemical properties and bioavailability. Several studies in rats and mice and in humans indicate that arsenite and arsenate present in drinking water are rapidly and nearly completely (about 95 %) absorbed after ingestion (ATSDR, 2007). However, the absorption of ingested inorganic arsenic varies, depending on the solubility of the arsenical compounds (the more water soluble the compound, the greater its absorption), the presence of other food constituents and nutrients in the gastrointestinal tract, and on the food matrix itself (EFSA, 2010).

 

Dermal:

In an in vitro human skin permeation study with arsenic acid, a dermal absorption rate of 0.93% was obtained; in addition, 0.98% of the dose were retained in skin after washing. As a consequence, a conservative dermal absorption rate of max. 2% may be considered for risk assessment via this route.

 

Inhalation:

Deposition and subsequent absorption of diarsenic trioxide in the lungs may be expected to be dependent on particle size: respirable particles (0.1 -1 µm) are carried further into the lungs where they are likely to be absorbed quickly, whereas larger particles will be translocated to the gut. However, based on the high oral bioavailability of soluble As(III) substances, complete systemic bioavailability can be assumed.

 

Distribution:

In the bloodstream, arsenic is distributed between the plasma and the erythrocytes, in which it is bound to haemoglobin. Arsenite and arsenate ions are readily transported into cells: arsenite by aquaglycoporins 7 and 9 which normally transport water and glycerol, and arsenate by phosphate transporters. In most species, residue levels following uptake are initially elevated in liver, kidney, spleen and lung, but several weeks later, arsenic is translocated to hair, nails and skin. Residual levels in animals tended to be higher for arsenite than arsenate. Arsenic is readily methylated in the body, and methylarsonate is the predominant metabolite in kidneys, whereas dimethylarsinate is the predominant metabolite in lungs. It is particularly worthy of note that rats differ from most mammalian species by accumulating arsenic in erythrocytes, likely by the binding of trivalent arsenic species to cysteine components of haemoglobin, with the binding affinity of trivalent arsenic species to red blood cells estimated to be 15-30-fold higher in rats than in humans (EFSA, 2010).

 

Placental transfer:

Arsenic readily passes through the placenta of mammals and humans, resulting in similar exposure levels both in fetuses and mothers. Inorganic arsenic as well as its methylated metabolites (methylarsonate and dimethylarsinate) pass through the placenta. In newborn babies of women exposed to arsenic via drinking water in Argentina, essentially all arsenic in plasma and urine was in the form of dimethylarsinate, suggesting that it is mainly this metabolite that reaches the foetal circulation in late gestational phases. The metabolic methylation of arsenic via one-carbon metabolism increases in women during pregnancy, which is why the human foetus is likely to be exposed to more inorganic arsenic and methylarsonate in early gestation (EFSA, 2010).

 

Transfer via mother’s milk:

In contrast to the rapid transfer of arsenic to the fetus, very little arsenic is excreted in breast milk: Argentinian women exposed to about 200 μg/L arsenic in their drinking water showed very low excretion in breast milk (ca. 3 μg/L). A study in Bangladesh indicated very low arsenic concentrations in breast-milk samples (median 1 μg/kg; range 0.25-19 μg/kg) despite high arsenic exposures from drinking water (about 50 μg/L). It is assumed that the small amounts of arsenic passing to milk are almost entirely inorganic, with efficient maternal methylation of arsenic likely to protect against excretion via breast milk (EFSA, 2010).

 

Metabolism:

In most mammalian species, including humans, the inorganic arsenicals are extensively biotransformed and excreted mainly as their metabolites. Arsenate enters the cell via the phosphate carrier system, and can be biotransformed enzymatically to arsenite via glutathione reductase. In mammals, arsenite directly undergoes oxidative methylation to a high degree in liver. There are considerable differences between species in arsenic biotransformation: most studied animals are more efficient in methylating arsenic to dimethylarsinate than humans, except primates which have been shown not to methylate arsenic at all (EFSA, 2010).

 

Excretion

Arsenic and its metabolites are readily excreted predominantly via urine but also via and bile. Urinary excretion rates of 80% in 61 hr following oral doses and 30-80% in 4-5 days following parenteral doses have been measured in humans. Although rats tend to excrete arsenic and metabolites preferentially into bile, the major route of excretion of arsenic compounds in most mammalian species and humans is via urine, and dimethylarsinate is the primary urinary metabolite. In contrast to most other mammals, humans excrete appreciable amounts of methylarsonate in urine. The composition of urinary arsenic metabolites varies from person to person and has been interpreted to reflect arsenic methylation efficiency, with a typical profile of urinary arsenic metabolites consisting of 10-30 % inorganic arsenic, 10-20 % methylarsonate and 60-70 % dimethylarsinate (EFSA, 2010; ATSDR, 2007).

Buchet et al. (1981) studied the urinary elimination of arsenic metabolites in volunteers who ingested a single oral dose of arsenic (500 ug As) either as sodium arsenite (SA), monomethylarsonate (MMA) or cacodylate (DMA). The excretion rate increased in the order SA < DMA < MMA. After 4 days, the arsenic excreted in urine corresponded to 46, 78, and 75 % of the ingested doses, respectively. Based on these findings, an average of 60% of total arsenic intake is assumed to be excreted via urine.

PB-PK model for arsenic:

A physiologically based pharmacokinetic model for exposure to inorganic arsenic in hamsters and rabbits has been developed. (Mann, S. 1996a/b) The model in its present state simulates three routes of exposure to inorganic arsenic: oral intake, intravenous injection, and intratracheal instillation. It describes the tissue concentrations and the urinary and faecal excretions of the four arsenic metabolites: inorganic As(III) and As(V), methylarsonic acid, and dimethylarsinic acid. The model consists of five tissue compartments, chosen according to arsenic affinities: liver, kidneys, lungs, skin, and others. The model is based on physiological parameters, which were scaled according to body weight. When physiological parameters were not available, the data for the model were obtained by fitting (tissue affinity, absorption rate, and metabolic rate constants). The excretions of the arsenic metabolites in urine and faeces are simulated well with the model for both species. This toxicokinetic model for the oral exposure route was validated using data on urinary excretion after repeated oral exposure to As(III) as well as after exposure to inorganic As via drinking water. Absorption by inhalation is validated using data on urinary excretion after occupational exposure to arsenic trioxide dust and fumes. In both cases, the model gives satisfactory results for urinary excretion of the four As metabolites. The PB-PK model is also used in the description of the effects on the kinetics of exposure via different routes and for the simulation of various realistic exposure scenarios.The data presented substantiates the assumption that the systemic availability after ingestion is comparable to that after inhalation.