192 Applications and Occurrences of Heterocycles in Everyday Life
together with the known natural occurrence (or close analogy to naturals) of many, is considered when carrying out a
risk assessment. Taking the permitted levels of consumption of fl avours, and consideration of specifi c circumstances
of use in cosmetics and household goods and so on, and the results of some genotoxicity and general toxicity tests,
approved compounds are classifi ed as G.R.A.S. (Generally Regarded As Safe).
For fl avours, permitted levels (sometimes only a few ppm) of fl avouring additives are set by considering the consump-
tion of such compound types as natural components of food and setting a level for the additive that is a minor part of
the total. For example, in the USA (1999) the annual consumption of pyrazines naturally contained in food was about
350 000 kg, and synthetic 2000 kg.
For fragrances, the levels are set as concentrations (usually signifi cantly higher than food additives) in the fi nal com-
positions, and are based on an estimate of how much could be absorbed by skin contact, or cause signifi cant irritation.
F&Fs act at receptors (similarly to some drugs) and likewise show structure–activity relationships (SARs), where
relatively minor structural changes (including chirality) can produce very large changes in odour, intensity or ‘side
effects’. The potential hazards of using close structural analogy for safety prediction are demonstrated by photo-
toxicity caused by a (cosmetic) mixture of coumarins where, eventually, coumarin itself was shown to be the only
innocent party. The phototoxic analogues were 6- and 7-methylcoumarins and 3,4-dihydrocoumarin. (Coumarin
is not allowed as a food additive as there is a potential for hepatotoxicity, although some foods contain signifi cant
quantities naturally.)
Toxins
Non-nutritional natural constituents present in food plants that do not cause any problem for the normal population
can cause severe problems in susceptible sub-groups. An important example of this is favism, a serious haemolytic
disease, which results from the consumption of broad (fava) beans. It is caused by divicine, which is a direct haemo-
lytic agent in a group of people, primarily of Mediterranean origin, who have genetically determined low levels of a
particular enzyme.
A much more general problem is the contamination by toxins (mycotoxins) due to fungi growing on food, which
can lead to acute poisoning or longer term effects such as carcinogenesis. The oldest known example of this is ergot-
ism, caused by a fungus that affects growing grains (particularly rye), and is incorporated into the fl our during
milling. The causal agent is ergotamine, a lysergic acid amide, which leads to severe vasoconstriction in the limbs,
resulting in gangrene and death. The disease can be avoided by use of fungicides and careful inspection of the grain
before milling.
The most important mycotoxin is afl atoxin B 1 (the most toxic of the group), formed by a number of Aspergillus
species, which affect a number of foodstuffs but most famously peanuts and derived products such as peanut
butter. Growth of the fungus is favoured by warm, damp climates. Acute toxicity (severe liver damage) can occur,
usually in animals, but from a human viewpoint low dose chronic ingestion is a major cause of liver cancer in the
developing world.
A very different toxin, ochratoxin A, is produced by other Aspergillus species affecting badly stored foods, which
has caused occasional outbreaks of severe kidney disease in humans and is also thought to have wider long term
carcinogenic potential.