Diet – Liver is high in vitamin A. The liver of certain animals, including the polar bear, bearded seal, fish, walrus, and moose, are particularly toxic (see ). It has been estimated that consumption of 500 grams of polar bear liver would result in a toxic dose for a human. Supplements – Dietary supplements can be toxic when taken above recommended dosages. Types of toxicity Acute toxicity occurs over a period of hours or a few days, and is less of a problem than chronic toxicity. Chronic toxicity results from daily intakes greater than 25,000 IU for 6 years or longer and more than 100,000 IU for 6 months or longer. Mechanism Absorption and storage in the liver of retinol occur very efficiently until a pathologic condition develops. Delivery to tissues Absorption When ingested, 70–90% of preformed vitamin A is absorbed and used. According to a 2003 review, water-miscible, emulsified, and solid forms of vitamin A supplements are more toxic than oil-based supplement and liver sources. Storage 80–90% of the total body reserves of preformed vitamin A are in the liver (with 80–90% of this amount being stored in hepatic stellate cells and the remaining 10–20% being stored in hepatocytes). Fat is another significant storage site, while the lungs and kidneys may also be capable of storage. Transport Until recently, it was thought that the sole important retinoid delivery pathway to tissues involved retinol bound to retinol-binding protein (RBP4). More recent findings, however, indicate that retinoids can be delivered to tissues through multiple overlapping delivery pathways, involving chylomicrons, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), retinoic acid bound to albumin, water-soluble β-glucuronides of retinol and retinoic acid, and provitamin A carotenoids. The range of serum retinol concentrations under normal conditions is 1–3 μmol/L. Elevated amounts of retinyl ester (i.e., >10% of total circulating vitamin A) in the fasting state have been used as markers for chronic hypervitaminosis A in humans. Candidate mechanisms for this increase include decreased hepatic uptake of vitamin A and the leaking of esters into the bloodstream from saturated hepatic stellate cells. Effects Effects include increased bone turnover and altered metabolism of fat-soluble vitamins. More research is needed to fully elucidate the effects. Increased bone turnover Retinoic acid suppresses osteoblast activity and stimulates osteoclast formation in vitro, resulting in increased bone resorption and decreased bone formation. It is likely to exert this effect by binding to