8 Overdose or prolonged ingestion of over-the-counter non-steroidal anti-inflammatory drugs such as paracetamol (acetaminophen), acetylsalicylic acid (aspirin) and phenacetin can lead to necrosis of renal tissue, which is a common cause of life-threatening renal insufficiency. In West Germany in 1983 an average of 13% of patients who registered for hemodialysis had overdosed on analgesics (Niesink et al 1996). Acetylsalicylic acid is chemically related to methyl salicylate, a constituent of several essential oils, which can also cause renal problems if taken in excessive amounts. In a fatal poisoning incident, a 17-month-old child was given 4 mL of methyl salicylate in error. On autopsy, the kidneys were swollen and highly congested, with some degeneration of the tubules (Hughes RF 1932). Renal problems caused by essential oils in humans are rare and have all been associated with oral overdose. One teaspoon of wintergreen oil proved fatal in a child aged 22 months, with autopsy showing abnormalities in the heart, liver and kidneys (Eimas 1938; Kloss & Boeckman 1967). Kidney damage was seen on autopsy in children of 2 and 12 years, who died after being given 16 drops and 30 drops, respectively, of wormseed oil (Wolf IJ 1935). Wormseed oil is toxic even at low doses because of its depressant action on the heart, and toxic signs include significant renal damage (Van Lookeren Campagne 1939; Opdyke 1976 p. 713–715). In one of the few fatal cases of pennyroyal oil poisoning, the ingestion of an unknown quantity by a woman resulted in rapid destruction of the kidney tubules, with death following massive urea leakage into the blood (Vallance 1955). A 31-year-old man was hospitalized with renal failure after ingesting 10 mL of wormwood oil. He fully recovered after 17 days (Weisbord et al 1997). Severe damage to kidney tissue has also been observed in several cases of poisoning from high-dose parsley apiole ingestion (Lowenstein & Ballew 1958; Amerio et al 1968; Colalillo 1974). In each of these cases, the substances causing nephrotoxicity were not only taken in high doses, but they are all known to be toxic. Wormwood and wormseed oils should not be administered by any route, and pennyroyal, parsleyseed and wintergreen oils should not be taken by mouth, and have dermal use limits. In one rare instance, methyl salicylate toxicity was implicated as a cause of kidney damage after high-dose dermal administration and application of a heat pad (Heng 1987). Very high doses of some essential oils have been nephrotoxic in experimental animals. A single oral dose of rue oil at 400 mg/kg was fatal in guinea pigs due to liver, adrenal and kidney damage (Leung & Foster 2003). Severe liver and kidney damage have been seen in LD50 tests with essential oils of calamus and sassafras (Von Skramlik 1959; Abbot et al 1961). As with essential oils, some of their constituents are nephrotoxic to rodents after acute dosing. Sublethal oral doses of benzyl cyanide were nephrotoxic in rats, causing increased excretion of protein, amino acids and glucose (Guest et al 1982). p-Cresol is nephrotoxic in high doses by any route, and can cause uremia (Wu ML et al 1998a; Lesaffer et al 2001; De Smet et al 2003). Benzyl cyanide is only found in four absolutes (ginger lily, karo karoundé, orange flower and nasturtium), and p-cresol is only found in oils of birch tar and cade oils. There were histological changes in the kidneys of rats dosed by gavage with 73.5 mg/kg of cinnamaldehyde for 90 days, along with proteinuria, creatinuria, and increased activities of renal, serum and urinary enzymes. Animals were not affected by lower doses (Gowder & Devaraj 2008). Very high doses (4 mL/kg) of methyl salicylate, applied to the skin of rabbits, five days a week for up to 96 days, caused early deaths and kidney damage. Lower (but still high) doses, 0.5, 1.0, or 2.0 mL/kg, caused a higher than normal incidence of ‘spontaneous’ nephritis (Webb & Hansen 1963). Since all doses were toxic, no NOAEL was established. Some other esters show signs of moderate nephrotoxicity on subchronic oral dosing at high levels. When rats were given isobornyl acetate at 15, 90 or 270 mg/kg/day for 90 days, there were signs of nephrotoxicity at the two higher dose levels (Gaunt et al 1971). Rats were given octyl acetate, 5 days per week for 90 days, at 100, 500 or 1,000 mg/kg. After 45 days of dosing, effects seen in the high-dose group included increased kidney weight and, in males only, evidence of hydrocarbon nephropathy (Daughtrey et al 1989a). The NOAEL of 100 mg/kg is equivalent to a human adult dose of 14 g of Boswellia papyrifera oil. Alcohols can also produce renal effects in rodents at elevated doses. In a 90-day study, rats were given dietary cis-3-hexenol at 310, 1,250 and 5,000 ppm. No effects were seen at the lower two doses, but at the high dose, the relative kidney weight was increased in male rats (Opdyke 1974 p. 909–910). When male and female rats were administered 0, 25, 100 or 400 mg/kg of 3-octanol for 90 days by gavage, some kidney damage was seen in males at the two higher doses (Lindecrona et al 2003). Both cis-3-hexenol and 3-octanol are only very minor constituents of essential oils. When 400 mg/kg of terpinen-4-ol was administered orally to rats for 28 days there were no changes in function or morphology of the kidneys and therefore no nephrotoxicity (Schilcher & Leuschner 1997). This is equivalent to a human adult dose of about 65 g. When angelica root oil was given orally to rats for 56 days at 0.5, 1.0, 2.0 or 3.0 g/kg, there was weight loss and decreased activity at the higher two doses, and deaths were associated with severe liver and kidney damage (Von Skramlik 1959). These are massive doses for any substance, and it seems surprising that any rats would have even survived on them for so long. Juniper oil has been mentioned frequently in connection with kidney damage. It has been claimed that, when given orally, ‘juniper’ can irritate the kidneys, and that it is contraindicated in kidney disease. However, while other preparations made from juniper may be problematic in kidney disease, no evidence could be found to support this claim for the essential oil (see Juniper profile, Chapter 13). One investigation of the purported nephrotoxicity of juniper oil found none. Up to 1 g/kg was administered orally to rats for 28 days and no changes in kidney function or morphology were seen (Schilcher & Leuschner 1997).
The urinary system
Nephrotoxicity
Acute dosing
Subacute and subchronic dosing
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