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175. Anaphylaxis due to oranges
148
METHODS FOR ASSESSING TOXICITY
175. ANAPHYLAXIS D U E TO ORANGES There are 2 constituents of oranges which give rise to allergic responses, one in the juice and another in the seed. The allergen present in the seed produces more severe reactions than that in the juice (Rather et al. J. Pediat. 1953, 43, 421). A case of an acute allergic attack following the eating of oranges has been reported (Bendersky & Lupas, J. Amer. med. Ass. 1960, 173, 255). The present account describes another such case, in a woman who ate 2 oranges and 10 min later became very distressed with shortness of breath and marked general itching. Her blood pressure fell to a dangerously low level, 64/40 mm and her face, hands and feet became oedomatous and she collapsed. After receiving appropriate treatment, including an antihistamine, partial recovery occurred. Examination in hospital showed that left bundle branch block had developed. This was more evident on the 2nd day but by the 3rd day normal conduction was restored. Williamson, J. W. (1961). Anaphylactoid reaction to oranges. J. Fla. med. Ass. 48, 247.
M e t h o d s for Assessing Toxicity 176. RESULTS OF LONG- AND SHORTTERM FEEDING STUDIES Responsible industry has always considered that it should carry out adequate safety testing on food additives before marketing. More and more extensive work on a compound's safety is demanded nowadays, principally by the Food and Drug Administration of the United States, and may cost as much or more than the original development of the additive. In consequence the authors' critical study of the value of 90-day toxicity studies for predicting the results of 2-yr studies is of great interest. According to the American National Research Council Publication Principles and Procedures for Evaluating the Safety of Food Additives, a 90-day test provides 'an estimation of the result to be expected from lifetime repeated ingestion of the proposed additive'. Long-term feeding studies however are conducted on the premise that 'the lifetime ingestion of an additive in food by man cannot be predicted from experiments less stringent than lifetime feeding in a short-lived mammal'. In practice this is interpreted as 2 yr in the case of a rat. The results of short- and long-term tests are presented by the authors for 33 compounds in terms of: 1. The maximum dietary level of compounds which produced 'no effect' (for convenience the symbols Ms and M L a r e used here for the results of 90-day and 2-yr tests respectively). 2. The level which gave a 'minimum effect' (Es and E L respectively). In some cases there was no adverse effect at the highest level fed: thus E s or E L or both could not be determined. In 22 out of 33 compounds the ratios Es/E L and Ms/M L were compared. In a further 5, EL could not
be determined; the ratio Ms/M L is therefore a maximum, since Ms may be greater than the highest level fed. For a similar reason, where Es was not found (3 compounds), Ms/M L is a minimum. Finally in 3 compounds, neither E s nor E L was found and Ms/ML is inconclusive. In about half the cases the Ms/ML ratios were 2 or less; 32 of 33 compounds had ratios of 9 or less, the 33rd being an 'odd' compound indeed, with Ms/ML=12 and Es/EL=20. The authors conclude that the 100-fold margin of safety usually provided for in relation to ML should be ample when applied likewise to M s . They emphasize that it is not their intention to eliminate the 2-yr test but to ascertain that the 90-day results can be used as a means of predicting the outcome of the longer test. McCoUister, D. D. & Weft, Carrol S. (1961). Appli-
cation of the relationships between short-term and long-term dietary feeding studies. Div. Agr. Food Chem., Amer. chem. Soc., Chicago, September, 1961. 177. SHORT-TERM VERSUS LONG-TERM F E E D I N G TESTS We have previously reported on the instructive comparisons drawn by the authors, between the information derived from 90-day and 2-yr toxicity studies on 33 materials. May we stress again their very important conclusion that the short-term test results can be used "with measured confidence" in order to predict the 2-yr results. Now we have a further critical survey which seeks the most effective criteria of toxicity in these experiments. At least 36 criteria of effect had been noted; but some of the materials examined exercised no obvious toxic action, and hence in these experiments none of the criteria could be assessed as efficient. Only a few criteria were effective in delineating the lowest dosage at which toxic action was manifested, in the short as well as the 2-yr tests. These were: body weight gain, liver and kidney weights (as percentages of body weight) and histopathological changes in liver and kidney. In 21 comparisons of long-term tests, each carried out on both rats and dogs, dogs were in no instance more sensitive than rats. The authors therefore recommend that the 2-yr dog test be replaced by a 3-month test, in the course of which any special effects peculiar to dogs may be discovered and thereupon form the basis of additional long-term tests. [We need hardly stress the importance of this work, or urge most strongly that more groups who are the repositories of these sorts of data should undertake similar types of analysis. Given enough retrospective information of this sort, the authorities may be moved to take account of the needless waste of effort which all this unnecessary work involves!] Weil, C. S. (1962). Relationship between short-term and long-term dietary feeding studies. Design of an effective test. A paper presented to the Division of Agricultural and Food Chemistry of the Amer. chem. Soc., September 9-14, 1962.
METHODS FOR ASSESSING TOXICITY
175. ANAPHYLAXIS D U E TO ORANGES There are 2 constituents of oranges which give rise to allergic responses, one in the juice and another in the seed. The allergen present in the seed produces more severe reactions than that in the juice (Rather et al. J. Pediat. 1953, 43, 421). A case of an acute allergic attack following the eating of oranges has been reported (Bendersky & Lupas, J. Amer. med. Ass. 1960, 173, 255). The present account describes another such case, in a woman who ate 2 oranges and 10 min later became very distressed with shortness of breath and marked general itching. Her blood pressure fell to a dangerously low level, 64/40 mm and her face, hands and feet became oedomatous and she collapsed. After receiving appropriate treatment, including an antihistamine, partial recovery occurred. Examination in hospital showed that left bundle branch block had developed. This was more evident on the 2nd day but by the 3rd day normal conduction was restored. Williamson, J. W. (1961). Anaphylactoid reaction to oranges. J. Fla. med. Ass. 48, 247.
M e t h o d s for Assessing Toxicity 176. RESULTS OF LONG- AND SHORTTERM FEEDING STUDIES Responsible industry has always considered that it should carry out adequate safety testing on food additives before marketing. More and more extensive work on a compound's safety is demanded nowadays, principally by the Food and Drug Administration of the United States, and may cost as much or more than the original development of the additive. In consequence the authors' critical study of the value of 90-day toxicity studies for predicting the results of 2-yr studies is of great interest. According to the American National Research Council Publication Principles and Procedures for Evaluating the Safety of Food Additives, a 90-day test provides 'an estimation of the result to be expected from lifetime repeated ingestion of the proposed additive'. Long-term feeding studies however are conducted on the premise that 'the lifetime ingestion of an additive in food by man cannot be predicted from experiments less stringent than lifetime feeding in a short-lived mammal'. In practice this is interpreted as 2 yr in the case of a rat. The results of short- and long-term tests are presented by the authors for 33 compounds in terms of: 1. The maximum dietary level of compounds which produced 'no effect' (for convenience the symbols Ms and M L a r e used here for the results of 90-day and 2-yr tests respectively). 2. The level which gave a 'minimum effect' (Es and E L respectively). In some cases there was no adverse effect at the highest level fed: thus E s or E L or both could not be determined. In 22 out of 33 compounds the ratios Es/E L and Ms/M L were compared. In a further 5, EL could not
be determined; the ratio Ms/M L is therefore a maximum, since Ms may be greater than the highest level fed. For a similar reason, where Es was not found (3 compounds), Ms/M L is a minimum. Finally in 3 compounds, neither E s nor E L was found and Ms/ML is inconclusive. In about half the cases the Ms/ML ratios were 2 or less; 32 of 33 compounds had ratios of 9 or less, the 33rd being an 'odd' compound indeed, with Ms/ML=12 and Es/EL=20. The authors conclude that the 100-fold margin of safety usually provided for in relation to ML should be ample when applied likewise to M s . They emphasize that it is not their intention to eliminate the 2-yr test but to ascertain that the 90-day results can be used as a means of predicting the outcome of the longer test. McCoUister, D. D. & Weft, Carrol S. (1961). Appli-
cation of the relationships between short-term and long-term dietary feeding studies. Div. Agr. Food Chem., Amer. chem. Soc., Chicago, September, 1961. 177. SHORT-TERM VERSUS LONG-TERM F E E D I N G TESTS We have previously reported on the instructive comparisons drawn by the authors, between the information derived from 90-day and 2-yr toxicity studies on 33 materials. May we stress again their very important conclusion that the short-term test results can be used "with measured confidence" in order to predict the 2-yr results. Now we have a further critical survey which seeks the most effective criteria of toxicity in these experiments. At least 36 criteria of effect had been noted; but some of the materials examined exercised no obvious toxic action, and hence in these experiments none of the criteria could be assessed as efficient. Only a few criteria were effective in delineating the lowest dosage at which toxic action was manifested, in the short as well as the 2-yr tests. These were: body weight gain, liver and kidney weights (as percentages of body weight) and histopathological changes in liver and kidney. In 21 comparisons of long-term tests, each carried out on both rats and dogs, dogs were in no instance more sensitive than rats. The authors therefore recommend that the 2-yr dog test be replaced by a 3-month test, in the course of which any special effects peculiar to dogs may be discovered and thereupon form the basis of additional long-term tests. [We need hardly stress the importance of this work, or urge most strongly that more groups who are the repositories of these sorts of data should undertake similar types of analysis. Given enough retrospective information of this sort, the authorities may be moved to take account of the needless waste of effort which all this unnecessary work involves!] Weil, C. S. (1962). Relationship between short-term and long-term dietary feeding studies. Design of an effective test. A paper presented to the Division of Agricultural and Food Chemistry of the Amer. chem. Soc., September 9-14, 1962.