BRITISH MEDICAL JOURNAL
LONDON, SATURDAY 8 MARCH 1975
Alternatives to the Fluoridation of Water The presence of 1 part per million (p.p.m.) of fluoride in drinking water, whether as a natural constituent or added artificially, has been shown from innumerable surveys or experiments throughout the world to be the most effective and practicable means of reducing dental caries.1 2 Recently, however, in view of the organized opposition to fluoridation, alternative methods of providing the benefits of fluoride have been given more attention.3 The fluoridation of milk is being vigorously sponsored by the Borrow Dental Milk Foundation.4 This idea has been tested at Winterthur, Switzerland,5 6 where milk was fluoridated at 1 p.p.m. for the greater part of a trial on about 150 children and 139 controls, and at Baton Rouge, Louisiana, where the concentration was about 4 p.p.m.7 The Swiss experiment showed a reduction in caries of up to 3000 in the various age groups, and in Louisiana the reduction was 700/o among the admittedly small numbers (64 and 65) of children completing the study. Animal experiments show that though fluoride is absorbed slightly more slowly from milk than from water (presumably owing to interaction with the calcium of milk) the final percentage absorbed is almost the same82% from milk and 89% from water.8 9 A possible objection to fluoridated milk is that, apart from those attending nursery school, children under the age of five are relatively inaccessible. Though enamel is being formed at this age some data suggest that part of the effect of fluoride is exerted after eruption:'° if so, failure to receive it until primary school will be less important. Incidentally, the need for fluoride in early life does not mean that its benefits are enjoyed only by children-as the opponents of fluoride often assert. If taken during childhood its effect in reducing caries is detectable, though diminished, up to the age of 65.11-13 Experiments in Switzerland'4 and Hungary 15 show that salt is another successful vehicle for fluoride, though the concentrations used (200 mg and 250 mg of NaF/kg, respectively) provided adults with an average of only about 0*6 to 0 7 mg of fluoride daily compared with 1-1-5 mg from water, and the reduction in caries was less than with water. The required level seems to be 300 to 400 mg/kg, and doubts have been expressed as to whether young children would consume enough salt to receive an effective intake even at that high concentration. The main advantages of milk and salt as vehicles of fluoride is that freedom of choice is preserved and that the total quantity of fluoride required is much less than for the fluoridation of the whole water supply, of which less than 1% is used C BRITISH MEDICAL JOURNAL 1975. AR reproduction rights reserved.
for drinking. After some successful pilot experiments the water supply to some schools in the U.S.A. has been fluoridated (at about 5 p.p.m. to compensate for the absence of fluoride in the water at home), thus directing the fluoride to the age groups which make most efficient use of it. Tablets containing 1 mg of fluoride for children over 2, or 0-25 mg for proportional dosage of younger children, are available and effective,3 17 though the enthusiasm of comparatively few parents or children is likely to be sustained up to the age of 12. If the tablets are sucked slowly rather than swallowed whole the fluoride has both a marked local effect (with concentrations up to 100 p.p.m. in saliva) and a systemic effect. Tablets are contraindicated in areas with fluoride in the water, as fluoride ingested from two sources might lead to some enamel mottling. A disadvantage of tablets in the home is the possible accidental ingestion of several months' supply by an adventurous toddler.'8 The effect of prenatal fluoride tablets on caries in children has been tested, but its beneficial effect is slight or nonexistent.'7 This is not surprising as the placenta tends to restrict entry of fluoride into the fetus.19 Dentifrices containing sodium or stannous fluoride or sodium monofluorophosphate, usually at concentrations providing 01% (1000 p.p.m.) of fluoride, have been extensively tested clinically and are widely available. In most of the trials,20 21 without supervision of the use of the dentifrice, caries was reduced in children by about 20% with a greater effect (approximately 300%) on teeth erupting during the experiment (usually 3 years); with supervision the reductions were larger.2' Most of the data refer to children, but from the known property of fluoride to accumulate in dental plaque22 23 and in early carious lesions24 25 fluoride dentifrices may be expected to exert some protective effect at all ages. Too few comparisons of the different formulations have been made and the results have been too variable to decide which has the greatest effect on caries. The possible ingestion of fluoride by young children from dentifrices has been studied because they do not always spit out their toothpaste. Estimations on urinary fluoride concentrations and on the amount of dentifrice present in the fluids expectorated after tooth brushing have shown that as much as 1-2 g of dentifrice may be swallowed (containing 1 to 2 mg of fluoride in most fluoridated dentifrices), but this did not occur regularly in any of the children.2628 The occasional ingestion of this quantity is well within acceptable limits, particularly as the calcium salts present as abrasives in many NO. 5957 PAGE 535
536
BRITISH MEDICAL JOURNAL
dentifrices reduce fluoride absorption. Nevertheless, in areas with fluoridated water providing daily basal intakes of up to 1 mg the additional fluoride from occasional swallowing of dentifrices could, as with tablets, conceivably lead to some mild mottling. In fluoridated areas it has been suggested that the use of fluoride-containing dentifrice should be reduced to amounts the size of a pea among children too young to spit out and rinse reliably. Mouth rinsing with fluoride solutions, subsequently expectorated, was first shown to be effective and practicable in a large multigroup study in Gothenburg.29 Eight different preparations were compared, and daily rinsing with 0.050 sodium fluoride (225 p.p.m. F) gave the largest reduction in caries. Most Swedish children now participate in supervised fluoride rinsing programmes in school, and many thousands already do so in Britain-and since their effect is topical, rinses, like dentifrices, are of value in children after the teeth are fully formed and erupted. Rinses expose the mouth repeatedly to high concentrations of fluoride, and though their safety has been shown clinically3' and in animal experiments,32 it seems prudent not to use fluoride mouth washes in the presence of a lesion of the soft oral tissues. To be fully effective these methods must be used continuously. Surveys carried out two years after discontinuing the use of a dentifrice or mouth rinse containing fluoride showed that the considerable reduction in caries originally observed had largely disappeared.33 34 Other methods of topical fluoride treatment include the application by dental auxillary staff of a fluoride solution or gel to the teeth two or three times a year. Finally, several studies have shown that different methods of fluoride application can have an additive effect: for example, dentifrices and topical application supplement each other21 and the effect of fluoridated water.35 1
Fluorides and Human Health. Geneva, W.H.O., 1970. Caries Research, 1974, 8, Suppl. 1. Geddes, D. A. M., et al., British Dental_Journal, 1973, 134, 426. 4Borrow Dental Milk Foundation, The Fluoridation of Children's Milk. London, Kimpton, 1973. 5 Wirz, R., Schweizerische Monatschrift fur Zahnheilkunde, 1964, 74, 767. 6 Ziegler, E., Helvetica Paediatrica Acta, 1964, 19, 343. 7Rusoff, L. L., et al., American Journal of Clinical Nutrition, 1962, 11, 94. 8 Ericsson, Y., Acta Odontologica, Scandinavica 1958, 16, 51. 9 Muhler, J. C., and Weddle, D. A., Jtournal of Nutrition, 1955, 55, 347. 10 Kwant, G. W., et al., Netherlands Dental J3ournal, 1973, 80, Suppl. 9, 6. 11 Murray, J. J., British DentalJournal, 1971, 131, 391. 12 Murray, J. J., British DentalJournal, 1971, 131, 437. 13 Murray, J. J., British DentalJournal, 1971, 131, 487. 14 Marthaler, T. M., and Schenardi, C., Helvetica Odontologica Acta, 1962, 6, 1. 15 Toth, K., Caries Research, 1973, 7, 269. 16 Heifetz, S. B., and Horiwitz, H. S.,Journal of American Dental Association, 1974, 88, 352. 17 Marthaler, T. M., Helvetica Odontologica Acta, 1969, 13, 1. 18 British 1972, 4, 785. 19 Gedalia, I., Fluorides and Human Health, World Health Organisation, Geneva, 1970, p. 128. 20 Duckworth, R., British Dental3Journal, 1968, 124, 505. 21 Marthaler, T. M., Caries Research, 1971, 5, 343. 22 Dawes, C., et al., British 1965, 119, 164. 23 Jenkins, G. N., Edgar, W. M., and Ferguson, D. B., Archives Oral Biology, 1969, 14, 105. 24 Dowse, C. M., and Jenkins, G. N., Journal of Dental Research, 1957, 36, 2
3
Medical_Journal,
Dental_Journal,
2
816.
5Weatherell, J. A., Robinson, C., and Hallsworth, A. S., In Tooth Enamel II
Ed. Fearnhead, R. W., and Stack, M. V., John Wright and Sons Ltd., Bristol, 1971. Ericsson, Y., and Forsman, B., Caries Research, 1969, 3, 290. Hargreaves, J. A., Ingram, G. S., and Wagg, B. J., Caries Research, 1970, 4, 256. 28 Hargreaves, J. A., Ingram, G. S., and Wagg, B. J., Caries Research, 1972, 6, 237. 29 Torell, P., and Ericsson, Y., Acta Odontologica Scandinavica, 1965, 23,
26 27
287.
Aasenden, R., DePaola, P. F., and Brudevold, F., Archives Oral Biology, 1972, 17, 1705. 31 Birkeland, J. M., Jorkend, L., and Von der Fehr, F. R., Community Dentistry and Oral Epidemiology, 1973, 1, 17. 32 Branemark, P. I., Odontologisk Revy, 1967, 18, 273. 33 Koch, G., Odontologisk Revy, 1969, 20, 323. 34 Koch G., Caries Research, 1970, 4, 149. 35 Goaz, P. W., McElwaine, L. P., and Biswell, H. A., journal of Dental Research, 1966, 45, 286.
30
8
MARCH 1975
Paracetamol (Acetaminophen) and the Liver In 1965 two patients died from fulminant liver failure-both had taken a few days before their deaths a large overdose of paracetamol (known in the U.S.A. as acetaminophen) with suicidal intent.' A trickle of such cases has since increased to a disturbing stream,2 so that there are now annually in England and Wales about 1000 patients admitted to hospital with paracetamol poisoning, and some 3%0 of them die. In man2 and in several animal species3 large doses of paracetamol produce centrilobular necrosis of parenchymal liver cells, so that this drug is a predictable hepatotoxin, like carbon tetrachloride, bromobenzene, and ot-amanitin (the mushroom poison). The exact mode of action of even the earliest of these poisons to be recognized, carbon tetrachloride, is still debated; but much is already known about the metabolism and toxicity of paracetamol. Paracetamol is removed from blood by the liver with a plasma half-life time of about 2 hours.4 Within the liver cell most of a therapeutic dose is conjugated with glucuronic acid and sulphate,5 while smaller amounts are probably oxidized by the cytochrome P. 450 mixed-function-oxidase enzyme system and the resulting metabolites conjugated either with cysteine or with glutathione to form a mercapturic acid.6 A complex series of metabolites is therefore excreted in the urine.5 Hepatic conjugation of a drug usually detoxifies it, so which of these paracetamol compounds does the damage? Much recent work has come from the National Institutes of Health, Bethseda, where it has been shown that large doses of paracetamol are slowly bound to the hepatic endoplasmic reticulum, particularly in centrilobular cells. Pretreatment of mice with the hepatic enzyme-inducing drugs phenobarbitone and 3-methylcholanthrene increases this binding of paracetamol and its hepatotoxicity,7 while enzyme inhibitors or protein deprivation8 do the reverse. Phenobarbitone also increases the small proportion of a therapeutic dose of paracetamol that is excreted in urine as the mercapturate.6 The culprit seems likely to be one of the metabolites of paracetamol rather than paracetamol itself. Because of the similarity with the metabolism of bromobenzene, 9 suspicion rapidly fell on unidentified oxidized intermediates-those thought to be conjugated with cysteine and glutathione. Thus in mice poisoned with paracetamol the hepatic concentration of glutathione rapidly falls.'0 Prior depletion of the liver stores of glutathione either pharmacologically'0 or by protein deprivation8 increases the hepatotoxicity of paracetamol, while, conversely, pretreatment with cysteine or methionine, which are precursors of glutathione, decreases it.8 10 It looks, then, as if paracetamol is usually safely conjugated with sulphate and glucuronic acid, but that as the dose is increased either the amount of paracetamol that is oxidized simply increases to toxic levels or the safe pathways become exhausted and the toxic pathway becomes increasingly important. The toxic metabolites are neutralized by glutathione, which contains a sulphydryl group, until all the glutathione is used up, when other sulphydryl groups around the cell (such as are present in many enzymes) are attacked, and damage then occurs. The theory is attractive. Does it suggest an antidote for paracetamol poisoning? Once paracetamol has reached the liver damage might be prevented in four ways. Firstly, the uptake of the drug from blood by the liver might be inhibited in the same way as probenecid acts to reduce the uptake of
LONDON, SATURDAY 8 MARCH 1975
Alternatives to the Fluoridation of Water The presence of 1 part per million (p.p.m.) of fluoride in drinking water, whether as a natural constituent or added artificially, has been shown from innumerable surveys or experiments throughout the world to be the most effective and practicable means of reducing dental caries.1 2 Recently, however, in view of the organized opposition to fluoridation, alternative methods of providing the benefits of fluoride have been given more attention.3 The fluoridation of milk is being vigorously sponsored by the Borrow Dental Milk Foundation.4 This idea has been tested at Winterthur, Switzerland,5 6 where milk was fluoridated at 1 p.p.m. for the greater part of a trial on about 150 children and 139 controls, and at Baton Rouge, Louisiana, where the concentration was about 4 p.p.m.7 The Swiss experiment showed a reduction in caries of up to 3000 in the various age groups, and in Louisiana the reduction was 700/o among the admittedly small numbers (64 and 65) of children completing the study. Animal experiments show that though fluoride is absorbed slightly more slowly from milk than from water (presumably owing to interaction with the calcium of milk) the final percentage absorbed is almost the same82% from milk and 89% from water.8 9 A possible objection to fluoridated milk is that, apart from those attending nursery school, children under the age of five are relatively inaccessible. Though enamel is being formed at this age some data suggest that part of the effect of fluoride is exerted after eruption:'° if so, failure to receive it until primary school will be less important. Incidentally, the need for fluoride in early life does not mean that its benefits are enjoyed only by children-as the opponents of fluoride often assert. If taken during childhood its effect in reducing caries is detectable, though diminished, up to the age of 65.11-13 Experiments in Switzerland'4 and Hungary 15 show that salt is another successful vehicle for fluoride, though the concentrations used (200 mg and 250 mg of NaF/kg, respectively) provided adults with an average of only about 0*6 to 0 7 mg of fluoride daily compared with 1-1-5 mg from water, and the reduction in caries was less than with water. The required level seems to be 300 to 400 mg/kg, and doubts have been expressed as to whether young children would consume enough salt to receive an effective intake even at that high concentration. The main advantages of milk and salt as vehicles of fluoride is that freedom of choice is preserved and that the total quantity of fluoride required is much less than for the fluoridation of the whole water supply, of which less than 1% is used C BRITISH MEDICAL JOURNAL 1975. AR reproduction rights reserved.
for drinking. After some successful pilot experiments the water supply to some schools in the U.S.A. has been fluoridated (at about 5 p.p.m. to compensate for the absence of fluoride in the water at home), thus directing the fluoride to the age groups which make most efficient use of it. Tablets containing 1 mg of fluoride for children over 2, or 0-25 mg for proportional dosage of younger children, are available and effective,3 17 though the enthusiasm of comparatively few parents or children is likely to be sustained up to the age of 12. If the tablets are sucked slowly rather than swallowed whole the fluoride has both a marked local effect (with concentrations up to 100 p.p.m. in saliva) and a systemic effect. Tablets are contraindicated in areas with fluoride in the water, as fluoride ingested from two sources might lead to some enamel mottling. A disadvantage of tablets in the home is the possible accidental ingestion of several months' supply by an adventurous toddler.'8 The effect of prenatal fluoride tablets on caries in children has been tested, but its beneficial effect is slight or nonexistent.'7 This is not surprising as the placenta tends to restrict entry of fluoride into the fetus.19 Dentifrices containing sodium or stannous fluoride or sodium monofluorophosphate, usually at concentrations providing 01% (1000 p.p.m.) of fluoride, have been extensively tested clinically and are widely available. In most of the trials,20 21 without supervision of the use of the dentifrice, caries was reduced in children by about 20% with a greater effect (approximately 300%) on teeth erupting during the experiment (usually 3 years); with supervision the reductions were larger.2' Most of the data refer to children, but from the known property of fluoride to accumulate in dental plaque22 23 and in early carious lesions24 25 fluoride dentifrices may be expected to exert some protective effect at all ages. Too few comparisons of the different formulations have been made and the results have been too variable to decide which has the greatest effect on caries. The possible ingestion of fluoride by young children from dentifrices has been studied because they do not always spit out their toothpaste. Estimations on urinary fluoride concentrations and on the amount of dentifrice present in the fluids expectorated after tooth brushing have shown that as much as 1-2 g of dentifrice may be swallowed (containing 1 to 2 mg of fluoride in most fluoridated dentifrices), but this did not occur regularly in any of the children.2628 The occasional ingestion of this quantity is well within acceptable limits, particularly as the calcium salts present as abrasives in many NO. 5957 PAGE 535
536
BRITISH MEDICAL JOURNAL
dentifrices reduce fluoride absorption. Nevertheless, in areas with fluoridated water providing daily basal intakes of up to 1 mg the additional fluoride from occasional swallowing of dentifrices could, as with tablets, conceivably lead to some mild mottling. In fluoridated areas it has been suggested that the use of fluoride-containing dentifrice should be reduced to amounts the size of a pea among children too young to spit out and rinse reliably. Mouth rinsing with fluoride solutions, subsequently expectorated, was first shown to be effective and practicable in a large multigroup study in Gothenburg.29 Eight different preparations were compared, and daily rinsing with 0.050 sodium fluoride (225 p.p.m. F) gave the largest reduction in caries. Most Swedish children now participate in supervised fluoride rinsing programmes in school, and many thousands already do so in Britain-and since their effect is topical, rinses, like dentifrices, are of value in children after the teeth are fully formed and erupted. Rinses expose the mouth repeatedly to high concentrations of fluoride, and though their safety has been shown clinically3' and in animal experiments,32 it seems prudent not to use fluoride mouth washes in the presence of a lesion of the soft oral tissues. To be fully effective these methods must be used continuously. Surveys carried out two years after discontinuing the use of a dentifrice or mouth rinse containing fluoride showed that the considerable reduction in caries originally observed had largely disappeared.33 34 Other methods of topical fluoride treatment include the application by dental auxillary staff of a fluoride solution or gel to the teeth two or three times a year. Finally, several studies have shown that different methods of fluoride application can have an additive effect: for example, dentifrices and topical application supplement each other21 and the effect of fluoridated water.35 1
Fluorides and Human Health. Geneva, W.H.O., 1970. Caries Research, 1974, 8, Suppl. 1. Geddes, D. A. M., et al., British Dental_Journal, 1973, 134, 426. 4Borrow Dental Milk Foundation, The Fluoridation of Children's Milk. London, Kimpton, 1973. 5 Wirz, R., Schweizerische Monatschrift fur Zahnheilkunde, 1964, 74, 767. 6 Ziegler, E., Helvetica Paediatrica Acta, 1964, 19, 343. 7Rusoff, L. L., et al., American Journal of Clinical Nutrition, 1962, 11, 94. 8 Ericsson, Y., Acta Odontologica, Scandinavica 1958, 16, 51. 9 Muhler, J. C., and Weddle, D. A., Jtournal of Nutrition, 1955, 55, 347. 10 Kwant, G. W., et al., Netherlands Dental J3ournal, 1973, 80, Suppl. 9, 6. 11 Murray, J. J., British DentalJournal, 1971, 131, 391. 12 Murray, J. J., British DentalJournal, 1971, 131, 437. 13 Murray, J. J., British DentalJournal, 1971, 131, 487. 14 Marthaler, T. M., and Schenardi, C., Helvetica Odontologica Acta, 1962, 6, 1. 15 Toth, K., Caries Research, 1973, 7, 269. 16 Heifetz, S. B., and Horiwitz, H. S.,Journal of American Dental Association, 1974, 88, 352. 17 Marthaler, T. M., Helvetica Odontologica Acta, 1969, 13, 1. 18 British 1972, 4, 785. 19 Gedalia, I., Fluorides and Human Health, World Health Organisation, Geneva, 1970, p. 128. 20 Duckworth, R., British Dental3Journal, 1968, 124, 505. 21 Marthaler, T. M., Caries Research, 1971, 5, 343. 22 Dawes, C., et al., British 1965, 119, 164. 23 Jenkins, G. N., Edgar, W. M., and Ferguson, D. B., Archives Oral Biology, 1969, 14, 105. 24 Dowse, C. M., and Jenkins, G. N., Journal of Dental Research, 1957, 36, 2
3
Medical_Journal,
Dental_Journal,
2
816.
5Weatherell, J. A., Robinson, C., and Hallsworth, A. S., In Tooth Enamel II
Ed. Fearnhead, R. W., and Stack, M. V., John Wright and Sons Ltd., Bristol, 1971. Ericsson, Y., and Forsman, B., Caries Research, 1969, 3, 290. Hargreaves, J. A., Ingram, G. S., and Wagg, B. J., Caries Research, 1970, 4, 256. 28 Hargreaves, J. A., Ingram, G. S., and Wagg, B. J., Caries Research, 1972, 6, 237. 29 Torell, P., and Ericsson, Y., Acta Odontologica Scandinavica, 1965, 23,
26 27
287.
Aasenden, R., DePaola, P. F., and Brudevold, F., Archives Oral Biology, 1972, 17, 1705. 31 Birkeland, J. M., Jorkend, L., and Von der Fehr, F. R., Community Dentistry and Oral Epidemiology, 1973, 1, 17. 32 Branemark, P. I., Odontologisk Revy, 1967, 18, 273. 33 Koch, G., Odontologisk Revy, 1969, 20, 323. 34 Koch G., Caries Research, 1970, 4, 149. 35 Goaz, P. W., McElwaine, L. P., and Biswell, H. A., journal of Dental Research, 1966, 45, 286.
30
8
MARCH 1975
Paracetamol (Acetaminophen) and the Liver In 1965 two patients died from fulminant liver failure-both had taken a few days before their deaths a large overdose of paracetamol (known in the U.S.A. as acetaminophen) with suicidal intent.' A trickle of such cases has since increased to a disturbing stream,2 so that there are now annually in England and Wales about 1000 patients admitted to hospital with paracetamol poisoning, and some 3%0 of them die. In man2 and in several animal species3 large doses of paracetamol produce centrilobular necrosis of parenchymal liver cells, so that this drug is a predictable hepatotoxin, like carbon tetrachloride, bromobenzene, and ot-amanitin (the mushroom poison). The exact mode of action of even the earliest of these poisons to be recognized, carbon tetrachloride, is still debated; but much is already known about the metabolism and toxicity of paracetamol. Paracetamol is removed from blood by the liver with a plasma half-life time of about 2 hours.4 Within the liver cell most of a therapeutic dose is conjugated with glucuronic acid and sulphate,5 while smaller amounts are probably oxidized by the cytochrome P. 450 mixed-function-oxidase enzyme system and the resulting metabolites conjugated either with cysteine or with glutathione to form a mercapturic acid.6 A complex series of metabolites is therefore excreted in the urine.5 Hepatic conjugation of a drug usually detoxifies it, so which of these paracetamol compounds does the damage? Much recent work has come from the National Institutes of Health, Bethseda, where it has been shown that large doses of paracetamol are slowly bound to the hepatic endoplasmic reticulum, particularly in centrilobular cells. Pretreatment of mice with the hepatic enzyme-inducing drugs phenobarbitone and 3-methylcholanthrene increases this binding of paracetamol and its hepatotoxicity,7 while enzyme inhibitors or protein deprivation8 do the reverse. Phenobarbitone also increases the small proportion of a therapeutic dose of paracetamol that is excreted in urine as the mercapturate.6 The culprit seems likely to be one of the metabolites of paracetamol rather than paracetamol itself. Because of the similarity with the metabolism of bromobenzene, 9 suspicion rapidly fell on unidentified oxidized intermediates-those thought to be conjugated with cysteine and glutathione. Thus in mice poisoned with paracetamol the hepatic concentration of glutathione rapidly falls.'0 Prior depletion of the liver stores of glutathione either pharmacologically'0 or by protein deprivation8 increases the hepatotoxicity of paracetamol, while, conversely, pretreatment with cysteine or methionine, which are precursors of glutathione, decreases it.8 10 It looks, then, as if paracetamol is usually safely conjugated with sulphate and glucuronic acid, but that as the dose is increased either the amount of paracetamol that is oxidized simply increases to toxic levels or the safe pathways become exhausted and the toxic pathway becomes increasingly important. The toxic metabolites are neutralized by glutathione, which contains a sulphydryl group, until all the glutathione is used up, when other sulphydryl groups around the cell (such as are present in many enzymes) are attacked, and damage then occurs. The theory is attractive. Does it suggest an antidote for paracetamol poisoning? Once paracetamol has reached the liver damage might be prevented in four ways. Firstly, the uptake of the drug from blood by the liver might be inhibited in the same way as probenecid acts to reduce the uptake of
