Saccharin

• Saccharin was discovered in 1879
• In 1977, the Food and Drug Administration proposed a ban on the use of saccharin, based on a multi-generational study from the Canadian Health Protetection Branch that showed an increase in bladder tumors in second-generation male rats fed the substance. Methodological problems existed in this investigation and rats have not been validated as a true indicator of carcinogenicity in humans.
• In 1977, due to high demand for a low-calorie sweetener, the US Congress passed the Saccharin Study and Labeling Act, which placed an 18-month moratorium on the ban against the use of saccharin, until additional research on its safety could be conducted. The act was extended in 1979, 1981, 1983 and more recently in June 1985. The act and extensions required more toxicological research and a warning label on all saccharin-containing foods, stating ”Use of this product may be hazardous to your health. This product contains saccharin which has been determined to cause cancer in laboratory animals."
• To date, numerous biochemical and epidemiologic studies in humans have not demonstrated carcinogenesis and saccharin is currently available for consumption
• To clarify the issue for clinicians, the Council on Scientific Affairs of the American Medical Association reviewed the available data up to 1985 and concluded, “because epidemiologic studies provide no evidence of increased risk of bladder cancer among users of artificial sweeteners, including saccharin and because there is no ideal artificial sweetener, saccharin should continue to be available as a food additive." However, based on the limited amount of information available, the report advised “careful consideration of saccharin use by young children and pregnant women.” Saccharin should not be recommended for use during the pre-conception and periconception periods.
  

Aspartame

• Aspartame was discovered in 1965
• Aspartame, the methyl ester of the amino acids 1-phenylalanine and aspartic acid, is a nutritive sweetener
• In determining whether aspartame is safe to use during pregnancy, a clinician must consider the implications of ingesting amino acids and aspartyl-phenylalanine diketopiperazine (DKP), which is the major decomposition product
• There appears to be little or no absorption of the intact dipeptide aspartame or DKP. Once absorbed into the portal circulation, all three compounds will be metabolized or excreted.

Aspartate

• Plasma concentrations of aspartate in humans, after doses of 34mg per kg of aspartame or 13mg per kg of aspartate, with no significant changes up to 24 hours after ingestion. Studies have indicated rapid metabolism. Even at abuse levels, 100mg to 200mg per kg plasma, aspartate concentrations remain below normal post-prandial adult oral feeding concentrations.
• During pregnancy, neither aspartic acid nor glutamic acid crosses the placenta to any significant degree
• Rhesus monkeys given aspartate at 10mg per kg per hour demonstrated minimal placental transfer
• It is almost impossible for humans to ingest aspartame in quantities sufficient to increase maternal plasma aspartate levels to values that would allow transfer of significant quantities of aspartate to the fetal circulation.

Methanol

• Upon ingestion of aspartame, it is broken down into methanol. Ingested methanol is metabolized by the enzyme alcohol; dehydrogenase into formaldehyde, which is oxidized into formic acid, the metabolite responsible for the ocular damage seen in methanol poisoning. 
• A bolus consumption of 200mg per kg of aspartame (equivalent to 20mg of methanol per kg of body weight and to a 60kg person’s consuming about 60 cans of soda a single sitting) failed to result in a detectable increase in the level of blood formate, while urine formate was significantly increased. The rate of formate synthesis did not exceed the rate of its excretion.  
• Little is known about the placental transfer and fetal effects of methanol. Based on the small quantity of methanol available from aspartame (a can of aspartame-sweetened soda contains about the same amount of methanol as a banana and less than many fruit juices) and the impossibility of overdosage, this metabolite appears safe for women.

Phenylalanine

• Phenylalanine is an essential amino acid that is required for protein synthesis as well as numerous metabolic functions
• In one out of 15,000 persons (who inherit two autosomal recessive genes), activity of the enzyme phenylalanine hydroxylases, which converts phenylalanine into tyrosine in the liver, is virtually absent. The outcome is an accumulation of phenylalanine and its metabolites in the blood and tissues of the infant, resulting in clinical manifestations of the disease phenylketonuria (PKU). Sustained high levels of plasma phenylalanine are associated with severe fetal compromise. This component of aspartame presents the most concern for the obstetrician.
• In humans, the fetal-to-maternal ratio of phenylalanine appears to be about 2:1. Conditions that elevate the maternal plasma phenylalanine concentration have about twice that effect on the fetal plasma phenylalanine concentration.
• Fasting plasma concentrations of phenylalanine in normal women are about 30umol to 50umol per L (0.5mg to 0.8mg per dL).

Does Aspartame Ingestion Increase Plasma Phenylalanine Concentrations Sufficiently to Have an Adverse Effect on the Fetus?

• Levy and Waisbren evaluated the effect of aspartame consumption by normal pregnant women and those heterozygous for phenylketonuria
• They demonstrated that severe retardation in the infant was present when the maternal blood phenylalanine level exceeded 1,100umol per L (18mg per dL) and microcephaly was present only when maternal blood phenylalanine level exceeded 1,200umol per L (20mg per dL). Maternal blood phenylalanine levels less than 600umol per L (10mg per dL) were not associated with decreased intelligence in the offspring.
• In chronic dose studies (13 to 28 weeks), which included healthy children and adolescents, young persons during weight reduction and non-insulin dependent diabetic and phenyketonuric heterozygous adults, there were no major changes in phenylalanine concentrations when large doses of aspartame were given daily. With repeated doses of aspartame (10mg per kg, equal to three 12oz cans of aspartame-sweetened soda) at two hour intervals for six hours, blood phenylalanine concentrations returned to baseline within the two-hour interval.
• Even at the highest intake phenylalanine from aspartame is minimal as compared to that contributed by dietary protein.

Aspartame and Pregnancy

All the data indicate that this component appears to be safe during pregnancy for normal women as well as for those heterozygous for PKU. A pregnant women homozygous for PKU must consider aspartame an additional source of phenylalanine.

Four articles site issues with the safety of saccharin in rats (two), monkeys (one) and humans (one), with the following results:

Animal and Human Studies Summary

• A review of four articles demonstrated that aspartate does not cross the placenta to any significant degree in human or animal models.

Methanol

Due to small amounts of methanol available from aspartame, it is concluded that the metabolite appears safe for pregnant women. Phenylalanine PKU and abnormality in the body’s ability to convert phenylalanine into tyrosine is of concern for the developing fetus. This issue raised the question: Will the ingestion of aspartame cause an increase in plasma phenylalanine concentration, resulting in an adverse effect on the fetus?

Steginik LD, 1984, studied the use of aspartame and concluded that even if a 70kg person were to abuse aspartame (injecting 100mg per kg in a single dose) the mean peak plasma phenylalanine concentrations would be below the sustained level associated with a fetal effect. It was concluded by this author that even at the highest level of intake, phenylalanine from aspartame is minimal, compared to that contributed by dietary protein. The author notes very little study during pregnancy has occurred pertaining to aspartame, compared to saccharin. Issues that are of concern pertain to embryogenesis, teratogenesis and central nervous system damage.

The article referenced 20 studies, evaluating the effects on fertility, conception rates, embryotoxicity, tetotoxidity and teratogenesis, with no significant treatment effects noted in rats and rabbits. Neonatal monkeys were studied, with no differences seen in neuropathologic hypothalamic exams. One study noted infant macaques were fed up to 3,000mg per kd per day or aspartame in a liquid formula for nine months and exhibited no convulsions, seizures, shudders or other abnormal neurologic behavior during administration of the experimental diet or the year after it occurred.