RELIS database 2002; spm.nr. 120, RELIS Øst
Dato for henvendelse: 15.07.2002
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SPØRSMÅL: Hvor mye vet man om sikkerheten ved bruk av cyklamat, aspartam og sakkarin i svangerskap.
Spørsmål sakset fra Eyr, svar også lagt ut her (http://www.uib.no/isf/eyr/eyr.htm).
Kort oppsummering, vesentlig fra referanse 1. Informasjon fra Micromedex (2) er kopiert nedenfor. Referanser ikke inkludert.
Stoffene er plassert i kategori C i USA, det betyr at dyrestudier har vist teratogene effekter eller effekter på fosterutvikling, men at det ikke er gjort kontrollerte studier på kvinner eller det er hverken dyre- eller humanstudier.
Ingen risiko hos 'normale' mødre eller mødre som er heterozygote for eller har PKU (fenylketonuri). Forhøyede plasmakonsentrasjoner av fenylalanin er assosiert med fostertoksisitet. Det er ikke kjent om det eksisterer en toksisk grenseverdi eller om nevrotoksisitet er lineær med serumkonsentrasjon av fenylalanin. Kvinner med PKU må kontrollere sitt inntak av fenylalaninholdige matvarer. Fordi aspartam er en (mindre viktig) kilde for fenylalanin, bør det tas hensyn til den i diettplanlegging. De andre komponentene i aspartam, metanol og aspartinsyre, og de forskjellige nedbrytningsproduktene er ikke toksiske i de doser det er snakk om. Micromedex (2) mener andre kilder er viktigere å kontrollere enn søtningsstoffet.
Ca 25 % av inntatt dose gjenfinnes i fosterblod. Det er ikke rapportert fosterskadelige effekter og det er ikke studert i kontrollerte studier. Cyklamat har vært mistenkt for å ha cytogenetiske effekter i humane lymfocytter. En gruppe forskere forsøkte å assosiere dette med en økt incidens av misdannelser og atferdsproblemer, men kunne ikke bekrefte en slik sammenheng.
Her er det ev. karsinogen effekt (blærekreft) man er bekymret for. Går i utstrakt grad over i foster og utskilles langsomt slik at det er fare for akkumulering. Fordi det er begrenset med informasjon om risiko in utero, bør inntak under svangerskap unngås.
Ingen data på ev. fosterskadelig effekt. Usannsynlig at det er fosterskadelig i aktuelle doser.
Micromedex. Reprotox. Vol 113, exp. 09/02
ASPARTAME (l-aspartyl-l-phenylalanine methyl ester) is a dipeptide ester composed of phenylalanine and aspartic acid that is used as a low calorie sweetener. The available animal studies have not associated this agent with an increased incidence of congenital defects. Animal studies have found that brain lesions may be seen in rodents treated with extremely high doses of aspartame (g/kg body weight). Comparable doses, however, do not affect the brain morphology of infant monkeys, suggesting that primates are not as susceptible as rodents to this form of aspartame intoxication. Behavioral testing after maternal gavage doses of 1000 and 4000 mg/kg body wt has produced indications of impairments in odor-aversion performance in guinea pigs, and conflicting reports on possible adverse effects on the visual placing response in exposed mouse pups. We did not locate any clinical or epidemiologic studies that reported on adverse effects of this agent when used in pregnancy.
Theoretical concerns have been raised about the use of aspartame by pregnant women and young children. It has been shown that plasma phenylalanine (PA) levels are elevated after ingestion of aspartame. These data raise the issue of whether women homozygous or even heterozygous for phenylketonuria might develop PA levels toxic to the fetus following the intake of aspartame. PA is normally derived from the breakdown of proteins, and consumed in amounts of roughly 50 mg/kg/d. The intake of PA from aspartame is unlikely to be more than 10% of that amount. Thus, women at risk of developing hyperphenylalaninemia must avoid numerous other sources of phenylalanine, in addition to aspartame, and the presence of aspartame in their diet is a relatively minor concern in their PA economy.
SACCHARIN is a nonnutritive sweetener. There has been concern about possible genotoxicity of this agent since it has been shown to cause bladder tumors in rats. Studies on the chromosomes of male mice and their offspring, however, have failed to reveal an increase in chromosomal translocations associated with saccharin treatment.
A number of teratology studies have been performed in animals using high doses of saccharin. Negative results have been documented in mice, rats, and rabbits. One group, however, has noted an increase in eye malformations in rats exposed prenatally to commercial saccharin preparations. This effect was believed to be due to contaminants of the preparations. The possibility of transplacental carcinogenicity of saccharin in rats was shown in one study where 7.5% dietary saccharin given to pregnant rats caused bladder tumors in the offspring; however, another study using up to 5 g/kg saccharin by gavage on specific days during pregnancy did not show evidence of transplacental carcinogenesis in rats.
The issue of transplacental carcinogenesis in humans was addressed in a survey on the incidence of bladder cancer in people born in Denmark during the years 1941 through 1945 compared to people born during 1931 through 1940. The rationale for this survey was the wartime shortage of sugar and consequent increase in saccharin use. No difference was found in rates of bladder cancer in the two groups.
Saccharin is known to cross the human placenta at term. The placental transfer of saccharin has also been studied in rhesus monkeys. This study indicated that the elimination of saccharin is much slower in the fetus than in the adult, with fetal saccharin remaining at detectable levels after maternal serum levels became negligible. Thus, the slow clearance of saccharin by the fetus might result in considerable accumulation of this sweetener if it is ingested repeatedly by a mother. Because of this concern, and the possibility of undetected problems, the safety review on saccharin by the Council on Scientific Affairs of the American Medical Association included a note of caution regarding the use of saccharin during pregnancy, and some clinicians recommend saccharin not be used by pregnant patients because alternative methods are available to limit sugar consumption.
There are few data on possible male reproductive toxicity of saccharin. A study in male mice treated with up to 500 mg/kg/d for two weeks showed no adverse effects on fertility.
CYCLAMIC ACID is also known as hexamic acid. Cyclamate salts are used as nonnutritive sweeteners. One of the most common of the cyclamates is the sodium salt, marketed as Sucaryl sodium, Assugrin, and Sucrosa; however, barium, potassium, and calcium salts are also described. Calcium cyclamate has been found to be negative in the dominant lethal and heritable translocation tests in male mice.
Safety of cyclamate use during pregnancy is suggested by studies performed in rats, rabbits, mice, dogs, and nonhuman primates. Cyclamates cross the placenta in humans; however, adverse effects on the offspring have not been found.
SORBITOL (glucitol) is found in many berries and other fruits. It has a sweet taste and is used as a flavoring, particularly in pharmaceuticals. Sorbitol has a caloric value similar to that of sucrose (table sugar). Sorbitol levels are elevated in the fetuses of experimentally diabetic rats; however, this does not appear responsible for the increased incidence of birth defects seen in these offspring. Feeding of up to 10% sorbitol in the diet of rats over three generations failed to produce abnormalities of reproduction, development, or lactation. Administration of a solution of 40% sorbitol to pregnant women in the third trimester produced an increase in vascular responsiveness to angiotensin. This response, which is a hallmark of preeclampsia, was also seen following saline infusion and is unlikely to be specific for sorbitol. We have been unable to locate controlled studies on possible adverse human reproductive effects of sorbitol. Its prevalence in foodstuffs and its ready metabolism (largely to carbon dioxide) make it appear unlikely to be toxic at doses normally encountered.