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The Metabolism and Toxicology of Saccharin

July 2013
Info 1(1):14-19

Authors:

S.I.R. Okoduwa

NSBMB, Ahmadu University, Zaria, Nigeria

Solomon Ajide

Landmark University

Saccharin, one of the sweeteners in the world, is still regarded as a carcinogen and diabetic inducer in some parts of the world. Concern peaked in 1977, after publication of a study indicating an increased rate of bladder cancer in rats fed large doses of saccharin. In 1977, Canada banned saccharin while US-FDA also proposed a ban. In due course, US congress required all saccharin-containing foods to display a warning label indicating that saccharin may be carcinogenic. This resulted in the carcinogenicity, genotoxicity, hepatotoxicity and teratological studies of saccharin in animals including humans by the most highly reputable global health and credible science organizations worldwide. None of these studies ever showed a clear causal relationship between saccharin consumption and health risks in humans at normal dosage. Ultimately, the influential 1977 study was later criticized for the high dosages of saccharin that were given to test subject rats. Consequently, the US-FDA formally withdraws its 1977 proposal to ban the use of saccharin and the National Toxicity Program announced the delisting of saccharin as a carcinogen. Therefore, use of saccharin can bring about a healthy lifestyle free of calorie accumulation and the risk of obesity with its associated cardiovascular complications.

The Structure of saccharin.

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The structure of saccharin with its sweetness receptor site.

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Figures - uploaded by S.I.R. Okoduwa

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Infohealth Awareness Article

Mini-Review Vol 1, (1): Jun. 2013, pp 14-19

THE METABOLISM AND TOXICOLOGY OF SACCHARIN

1*S.I.R. Okoduwa; 2G.U. Ebiloma; 1J. Baba and 3 S. Ajide.

1Department of Biochemistry, Ahmadu Bello University, Zaria-Nigeria.

2Department of Biochemistry, Kogi State University, Anyigba, Kogi State Nigeria

3Department of Animal Science, Ahmadu Bello University, Zaria-Nigeria.

Accepted 07 June, 2013

ABSTRACT

Saccharin, one of the sweeteners in the world, is still regarded as a carcinogen and diabetic inducer in some

parts of the world. Concern peaked in 1977, after publication of a study indicating an increased rate of bladder

cancer in rats fed large doses of saccharin. In 1977, Canada banned saccharin while US-FDA also proposed a

ban. In due course, US congress required all saccharin-containing foods to display a warning label indicating

that saccharin may be carcinogenic. This resulted in the carcinogenicity, genotoxicity, hepatotoxicity and

teratological studies of saccharin in animals including humans by the most highly reputable global health and

credible science organizations worldwide. None of these studies ever showed a clear causal relationship between

saccharin consumption and health risks in humans at normal dosage. Ultimately, the influential 1977 study was

later criticized for the high dosages of saccharin that were given to test subject rats. Consequently, the US-FDA

formally withdraws its 1977 proposal to ban the use of saccharin and the National Toxicity Program announced

the delisting of saccharin as a carcinogen. Therefore, use of saccharin can bring about a healthy lifestyle free of

calorie accumulation and the risk of obesity with its associated cardiovascular complications.

Key Words: Saccharin, Carcinogen, Sweetener, Toxicity

INTRODUCTION

Saccharin, a petroleum derivative is a white crystalline

artificial sweetener that is about 200 to 700 times sweeter

than sucrose. It is one of the most studied food ingredients

and the foundation of many low-calorie and sugar-free

products around the world. It is one of the oldest of non-

nutritive sweeteners, whose use is allowed in the US, but

banned in other countries [1, 2, 3,4].

Origin of Saccharin: Saccharin was serendipitously

discovered in 1879 by Constantine Fahlberg, a chemist of

Johns Hopkins University as one of the first artificial

sweeteners on earth.

*Okoduwa, S.I.R. is a Toxicologist/Medical Biochemist; and presently the

Director of Medical Research at Infohealth Awareness Group, Abuja -

Nigeria.

CORRESPONDENCE:

Tel: (+234) 08055-843-993; 0909-9640-143.

Email: stanley@sironigeria.com;

Website: http://sironigeria.com

This happened when he was researching the oxidative

mechanisms of toluenesulfonamide while working on coal

tar derivatives in the laboratory of Ira Remsen. Accidentally,

he spilled a chemical on his hand. Later on, while eating

dinner, Fahlberg noticed a more sweetness in the bread he

was eating, he licked his finger and noticed that the

substance had a sweet taste [5, 6, 2,7]. Through careful

examination, he traced the sweetness back to the chemical,

later named saccharin, by tasting various residues on his

hands and clothes and finally chemicals in the laboratory. In

1879 and 1880, Fahlberg and Remsen published articles on

benzoic sulfinide. Fahlberg described the methods of

producing this substance that he named saccharin when he

was in New York City working on his own in 1884 [5].

Since the time of saccharin discovery, a number of

compounds have been discovered and used as food additives

for their sweetening properties. Its use has been since 1900,

but obtained FDA approval in 1970 [7]. By 1907, saccharin

was used as a replacement for sugar in foods for diabetics.

A Publication Series By

SIRONigeria Global Limited

Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19

InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 15

Since it is not metabolized in the body for energy, saccharin

is classified as a non-caloric sweetener. By the 1960s it was

used on a massive scale in the "diet" soft drink industry [2].

Consequent upon sugar shortage during the World War I,

saccharin became widespread and commercialized. Since

saccharin is a calorie-free sweetener, its popularity further

increased during the 1960s and 1970s among dieters [2]. In

the United States, saccharin is often found in restaurants in

pink packets; the most popular brand is "Sweet 'N Low".

Saccharin is used to sweeten products such as drinks,

candies, medicines, and toothpaste, canned fruit, jams, salad

dressing, chewing gum, table top sweeteners, baked goods,

jams, and dessert toppings etc [2]

CHEMISTRY OF SACCHARIN

Structure of Saccharin: The chemical formula of saccharin

is C7H5NO3S and the basic substance in it is benzoic

sulfimide. It has a pKa value of about 2.0. It can be used to

prepare exclusively disubstituted amines from alkyl halides

using Gabriel synthesis. The chemical structure of saccharin

is diagrammatically represented Figure 1.

Figure 1. The Structure of saccharin.

Nature of Saccharin: Saccharin is a white crystalline solid

with a molecular mass of 183.18g mol-1 and a density of

0.828g/cm3. It has a melting point of 228.8 – 229.7oC. Even

though saccharin has about 200 – 700 times the sweetening

power of sucrose, yet it has an unpleasant bitter or metallic

aftertaste, especially at high concentrations.

Taste of Saccharin: It is still unclear as to the reason for the

sweet taste of saccharin. However, scientist has proposed

that it might be due to its shape which fit into the specific

receptor site in the taste buds. Evidence for this comes from

the fact that if the shape is modified slightly, say by

changing the H on the nitrogen to a methyl, the new

molecule no longer tastes sweet. Perhaps the specific taste

receptors it targets are peculiar to humans, in view of the fact

that bees or butterflies, which normally crave the sweetness

of nectar, do not treat it as a pleasing substance. [2]. The

figure 2 below shows the sweetness receptor with saccharin.

Figure 2: The structure of saccharin with its sweetness receptor site.

The region marked “AH+” has hydrogen available to

hydrogen bond to oxygen that is part of the sulfur group,

whereas, the area marked “B-” has a partially negative

oxygen avail.

Effect of Heat on Saccharin: Saccharin is stable to heat

unlike the newer artificial sweetener aspartame, but it does

not react chemically with other food ingredients. Blends of

saccharin with other sweeteners are often used to

compensate for each sweetener's weaknesses [5, 8].

Solubility in Water: The solubility of Saccharin in water is

about 1g per 290 ml. In its acidic form it is insoluble in

water. The sodium salt form is usually used as an artificial

sweetener. The calcium salt is also used at times, particularly

by people restricting their dietary sodium intake. Both salts

are highly water-soluble; usually about 0.67 grams per

milliliter water at room temperature. [5, 8].

Synthesis of Saccharin: Saccharin can be synthesized

through the initial reaction between toluene and

chlorosulfonic acid. It is then converted to a sulfonamide

with ammonia, and oxidized to a benzoic acid then heated to

form the cyclic imide [5, 9]. The yield from this method is

very low. An improve method was developed in 1950 at the

Maumee Chemical Company of Toledo. In this production

method, anthranilic acid successively reacts with nitrous

acid, sulfur dioxide, chlorine, and then ammonia to produce

saccharin. Another route begins with o-chlorotoluene. It is

also known as ortho sulfobenzoic acid [10]. A series of

different chemical impurities could find their way to the final

product, hence the most widely used methods for the

production of saccharin are the Remsen-Fahlberg and the

Maumee processes.

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InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 16

METABOLISM OF SACCHARIN

Ingestion: Upon ingestion, saccharin goes through the

human digestive system without being digested, for this

reason it is not absorbed or metabolized. It is excreted,

unchanged, via the kidneys. On this bases that saccharin is

not metabolized, the FDA of the United States considers this

compound safe [7]. Although saccharin has no food energy

value, yet it can trigger the release of insulin in humans and

rats due to its taste [11, 12, 13]

Absorption: The absorption of saccharin depends on

various factors, such as the pH value and the pKa of the

animal. In most animas including man, absorption of

saccharin occur rapidly with a pKa of about 2.0- 2.2.

Saccharin exists in acidic media predominantly in the

unionized form, which is the more readily absorbed form in

a number of animal species. In the stomach of rabbit and

guinea-pig, saccharin is absorbed completely at a pH of 1.9

and 1.4 respectively, when compared with the stomach of rat

at a pH 4.2 [14, 15]. In monkeys, and also most probably in

man, both gastric acidity and degree of absorption are

intermediate between those of the rabbit and guinea-pig on

one side, and the rat on the other [14]. Which means the

degree of absorption of saccharin could be dependent on

food intake which affects the acidity of the gastric contents.

Distribution and Excretion: Notable researcher, including

Lethco and wallace [16] studied the distribution of

radioactivity in organs and tissues of rats at various time

intervals (1, 2, 4, 8, 24, 48 and 72 hours) following a single

oral administration of (3-14C) saccharin (50 mg/kg).

Approximately one hour after dosing, Traces of radioactivity

were found in almost all organs. It was found that brain and

spleen contained only minute quantities of 14C., while

Kidney, urinary bladder and liver contained the highest

amount of 14C, which peaked at 4 and 8 hours. In

subsequent experiments, rinsing the bladders of the treated

rats with 8, 0.5 ml portions of a 0.9% saline solution, they

found that a significant portion of the 14C activity was

retained by or bound to the bladder tissue [16].

TOXICITY STUDY OF SACCHARIN

Carcinogenicity Study: Following the investigation

research report of Harvey W. Wiley that saccharin poses

digestive problem [17], worries arose among man regarding

the safety of saccharin. In responds to the issue by the then

president of the United States of American Theodore

Roosevelt (who was at the time dieting too on orders from

his medical doctor to lower his risk for diabetes) said to

Wiley Harvey that “Anyone who thinks saccharin is

dangerous is an idiot” [17].

The concern that saccharin might be an animal carcinogen

all through the “60s as suggested by various studies that was

conducted in experimental models peaked up in 1977 [17]

consequent upon the publication that saccharin increases the

rate of bladder cancer in rats fed with large doses of

saccharin. This led to the ban of saccharin in China and its

proposed ban in the United State by the US FDA. At the

time, saccharin was only artificial sweetener available in the

U.S and the proposed ban met with strong public opposition,

mostly by the diabetic persons. In the long run, the U.S.

congress placed a moratorium on the ban, requiring instead

that all saccharin-containing foods display a warning label

indicating that saccharin may be a carcinogen. Series of

experiments have been conducted on saccharin with some

showing a correlation between consumption and increased

bladder cancer and others showing no such correlation. An

obvious relationship between saccharin and health risks in

human subjects at normal doses have never been established

in any study till date, but the correlation between

consumption and cancer have been shown in some studies

[17].

The biological mechanism believed to be responsible for the

rats’ cancers has been shown to be inappropriate to humans,

as a result of the difference in urine composition between

rats and human. Many of the rat cancer may have been

caused by contamination from the rubber plungers inside

syringes, the rubber seals used may corrode when mixed

with certain fluids and decomposed rubber may have caused

the bad results. Others blame certain types of rats like the

Fischer 344 Rat which became a poor example specimen for

testing cancers when it was found out that these laboratory

animals developed cancer spontaneously, when injected with

pure water only [9]. The FDA of the U.S. in 1991, formally

withdraw its proposed 1977 ban on the use of saccharin. But

in 2000, the U.S congress repealed the law requiring

saccharin products to carry health warning labels.

Toxicological Study: Studies on saccharin exposure reveal

that it has both positive and negative effect, such as the

possibility to induce cancer in rats and dogs, hence the first

attem

banning saccharin came in 1911, when a group

of federal scientists categorized

as an

“adulteran

”

not

suitable for general use in foods,

though the

same group

later approved its use in

s “for invalids [18]. The

review conducted in 1983 by Arnold provide information on

two-generation saccharin bio-assays. In the researching of

the potential effects of substances, at least two generation

studies are beneficial. With respect to the studies, animals

were exposed to saccharin, at all stages of development (i.e.,

in uteri, during lactation, and in feed as an adult). Only three

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InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 17

studies of saccharin used a two-generation model, as at the

time of Arnold’s publication. These studies categorically

demonstrated that when rats were exposed to diets

containing 5% or 7.5% saccharin from the time of

conception to death, an increased frequency of urinary

bladder cancers was found, mostly in males. There was an

observation of the fact that saccharin is not metabolized, it is

nucleophilic and does not bind to DNA. But, it does suppress

humoral antibody production in rats. At dosages of 5% or

greater, saccharin does not act as a typical chemical

carcinogen, based on the theory that all carcinogens are

strong electrophilic agents [4]. The finding from the study

above lead to the prohibition of saccharin in Canada and a

proposed ban in the United States [6, 19].

In 1991, the U.S. withdrawn her proposed ban, but foods

containing saccharin were required to carry a warning label

[20, 19]. To indicate that “saccharin is a potential cancer

causing agent,” a warning label was placed on all products

containing saccharin. Current research showing the safety of

this product led to this decision being overturned in 2000

[21]. Though, a ban on saccharin still exists in Canada,

having considering the fact that series of toxicological

evidence and the lack of a consistent association in

epidemiological studies the Health Canada suggests that

carcinogenic effects of saccharin noted in rats are not

relevant to humans. Hence, they are considering re-listing

saccharin as a food additive in the Canadian Food and Drug

Regulations for use as a sweetener in the proposed food

categories [22, 19].

Hepatotoxicity Study: In 1992, Kumar, et al. reported that

saccharin posed no threat to liver function [23]. It was also

reported that in a patients who had elevated serum

concentrations of liver enzymes after the oral administration

of three different drugs, of which saccharin was the only

common constituents, re-exposure to pure saccharin

supported its role in the pathogenesis of liver damage in the

patients. The pathogenesis of saccharin hepatotoxicity in

these patients is unclear. Symptoms suggestive of

hypersensitivity were absent. Saccharin is not metabolized in

vivo, being in an almost unmodified form in the urine, and it

does not accumulate in the liver. The small amount of

saccharin (never exceeding 16 mg daily) taken by patients

underscores the idiosyncratic nature of the reaction [23, 24].

Teratology Study: Till date, the teratogenic study of

saccharin with mice has always been negative. In an

experiment conducted on feeding pregnant female rats with

diets containing 0.3% saccharin throughout the gestation

period shown that the pups from saccharin treated dams had

a 37.9% incidence of lens anomalies versus 12.4% incidence

for the control animals [25].

Genotoxicity Study: Several in-vitro and in vivo studies

have shown clastogenicity, specifically at high

concentrations in in-vitro studies [26, 27]. In several in-vitro

studies for induction of chromosomal aberrations in Chinese

hamster cells and in human lymphocytes, sodium saccharin

was found weakly positive [27, 28]. By and large weak

responses were observed in some in-vitro assays at the

chromosomal level. However, these were only seen in high

concentrations and it is possible that they are attributable to

ionic imbalances which are known to cause non-specific

effects. There are also conflicting reports from in vitro

studies, but some cases the materials use was found or

known to contain impurities or contaminants from the

manufacture of saccharin [29].

Epidemiological Study: Series of evidence comes from the

now numerous epidemiological studies on saccharin which

have included studies of groups consuming relatively high

levels of saccharin. In a reviews by Chappel, [30]; Elock and

Morgan, [31], it was indicated that there is no detectable

association between artificial sweetener consumption most in

particular saccharin and bladder cancer in humans. Various

epidemiological studies indicates no increase in the

occurrence of bladder tumours in human from the ingestion

of saccharin, including in individuals with the highest

consumption rate of artificial sweetened beverages and those

using saccharin as a table-top sweetener.

Beneficial Usage of Saccharin: All over the world, Food

and beverages industries have over the century found the use

of saccharin imperative due to its absence of carbohydrate

and no calorie value. For example, in Europe, the use of

saccharin became more considerable after the two world

wars. Several generations of Americans has made the use

saccharin an integral part of their daily lifestyle in the United

State. Most in particular, the diabetic individuals whose diets

require a restriction of caloric or carbohydrate intake. A

good number of health practitioners support the use of a non-

caloric sweetener like saccharin in weight reduction and for

people with diabetes [21].

According to the Calorie Control Council Research (CCC),

Health professionals believe saccharin is especially

beneficial to persons with diabetes and the obese, and helps

reduce dental cavities. According to opinion research, people

use saccharin to stay in better overall health, control weight

or maintain an attractive physical appearance. In another

report of the CCC, No low-calorie sweetener is perfect for

all uses. But, a range of sweeteners enables the development

of a much wider range of new, good-tasting, low-calorie

Okoduwa,et al., 2013 / Infohealth Awareness Article. Vol 1, No.1: PP 14-19

InfoHealth Awareness Article Vol 1 No 1 Jun. 2013 18

products to meet consumer demand. Also, an array of low-

calorie sweeteners provides products with increased stability,

improved taste, lower production costs and more choices for

the consumer [21].

Saccharin is important for a wide range of low-calorie and

sugar-free food and beverage applications. It is used in such

products like soft drinks, tabletop sweeteners, baked goods,

jams, chewing gum, canned fruit, candy, dessert toppings

and salad dressings. It is also used in cosmetic products,

vitamins and pharmaceuticals. One of the most popular uses

of saccharin is in the production of the product called “Sweet

'N Low®”, a tabletop sweetener in the United State [21,30].

GLOBAL REPORTS ON THE SAFETY OF

SACCHARIN

Over the years, series of researchers, corporate bodies and

individuals have worked on saccharin. The most highly

reputable global health and credible science organizations

have these comments to say with respect to the evaluation

and confirmation on the safety of saccharin as it relate to

human subjects.

The National Cancer Institute in its "Cancer Facts"

documents reviewed in 2009 stated that ‘epidemiological

studies do not provide clear evidence’ of saccharin’s link to

human cancer.

The World Cancer Research Fund Stated in the American

Institute for Cancer Research 2007 reported on page 143 that

the evidence from epidemiological studies does not suggest

that artificial sweeteners have a detectable effect on the risk

of any cancer [32].

The American Dietetic Association "Use of Nutritive and

Non-nutritive Sweeteners" position statement, on July 1993.

States that "Evidence gathered from the numerous animal

and human studies of saccharin does not suggest that there is

any significant risk to the human population from the normal

use of saccharin.

Members of the British Medical Association Advised in

the British Medical Journal, that "The major benefits of

saccharin are; an improved quality of life, low cost, and

stability at warm temperatures. A small risk for bladder

cancer continues to be found in male rats exposed to high

doses of saccharin. However, epidemiologic studies show no

evidence of a carcinogenic effect in man [33].

The Health Protection Branch of the Health and Welfare

Canada, on December 5, 1991 declared that

"Epidemiological studies have also not established any

evidence that bladder cancer in man is associated with

saccharin intake [33, 34].

CONCLUSION

The Joint Expert Committee on Food Additives (JECFA) of

the World Health Organization and the Scientific Committee

for Food of the European Union has reviewed and certified

the safety of saccharin. As of today, saccharin is approved in

more than 100 countries around the world. It can therefore

be recommended as one of the very best choice for diabetic

patients and those dieting. Therefore, use of saccharin can

bring about a healthy lifestyle free of calorie accumulation

and the risk of obesity with its associated cardiovascular

complications.

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This article is a postgraduate research seminar presented by the first author to the Department of Biochemistry, Ahmadu Bello University, Zaria-

Nigeria, in partial fulfillment for the assessment of Nutritional and Environmental Toxicology in 2010. Infohealth Awareness Article is a Copyright of

InfoHealth Awareness Group, a Non-Profit Organisation aimed at eradicating preventable diseases and hereditary disorders in Nigeria in order to have

Review and synthesis of data on the potential environmental impact of artificial sweeteners

Article

Full-text available

Oct 2021

EFSA is implementing evidence‐based risk assessments for the re‐evaluation of certain sweeteners. The aim of this work was to ensure that, as part of the preparatory work done by EFSA to support its Panel on Food Additives and Flavourings (FAF) in reaching conclusions on the safety of permitted food additives, relevant information on the environmental risks associated with the use of the artificial sweeteners are identified. In the context of this re‐evaluation process the following substances used as sweeteners were considered: acesulfame‐K (E 950), salt of aspartame‐acesulfame (E 962), sucralose (E 955), saccharins (E 954), thaumatin (E 957), neohesperidine DC (E 959), neotame (E 961), cyclamates (E 952) and the polyol sweeteners (sorbitols (E 420); mannitol (E 421); isomalt (E 953); maltitols (E 965); lactitol (E 966); xylitol (E 967) and erythritol (E 968)). Data was collated using a systematic review approach. Generally, the data identified was extremely limited particularly with respect to neohesperidine DC, neotame, thaumatin and the polyol sweeteners. However, there was also limited evidence to suggest their widespread occurrence in the environment. With respect to acesulfame‐K, sucralose, cyclamates and saccharin multiple studies were identified that demonstrate the widespread distribution of these sweeteners in surface waters, groundwaters, coastal and marine waters. There are also studies showing their presence in drinking (tap) water supplies, rainwater and in atmospheric samples. However, these sweeteners do not appear to be highly toxic to aquatic species, at least not at environmental concentrations currently seen. The salt of aspartame‐acesulfame easily dissociates into its two component sweeteners in the human body and the environment and so the review process also considered aspartame despite it not being a specific focus of the regulatory review process. Whilst there is some evidence to suggest aspartame is toxic to aquatic species it is not detected at levels of concern in the environment.

A Review: Saccharin Discovery, Synthesis, and Applications

Article

Full-text available

May 2020

Saccharin is firstly synthesized in 1879. It is a very well-known as an inexpensive substitute for sugar as it is a non-caloric sweetener. The article shows the properties, use, metabolism and various synthesis and reactions of saccharine. Moreover, the toxicological reports explain that saccharin is mostly responsible for the bladder tumors observed in the male rats, the relationship between the consumption of saccharin and bladder cancer is afforded by epidemiological studies. The benefit-risk evaluation for saccharin is hardly to indicate. Saccharin is a sugar substitute, frequently used either in food industry, or in pharmaceutical formulations and even in tobacco products. The chemistry of saccharin is interesting because of it suspected carcinogenous character and the possible use as an antidote for metal poisoning. It appears prudent to evaluate their main properties and applications further.

Long-Term Saccharin Consumption and Increased Risk of Obesity, Diabetes, Hepatic Dysfunction, and Renal Impairment in Rats

Article

Full-text available

Oct 2019
MED LITH

Background and objectives: This study evaluated the effect of chronic consumption of saccharin on important physiological and biochemical parameters in rats. Materials and Methods: Male Wistar rats were used in this study and were divided into four groups: A control group and three experimental groups (groups 1, 2, and 3) were treated with different doses of saccharin at 2.5, 5, and 10 mg/kg, respectively. Each experimental group received sodium saccharin once per day for 120 days while the control group was treated with distilled water only. In addition to the evaluation of body weight, blood samples [total protein, albumin, glucose, lipid profile, alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), creatinine, and uric acid] and urine (isoprostane) were collected in zero time, and after 60 and 120 days for biochemical evaluation. Liver (catalase activity) and brain (8-hydroxy-2’-deoxyguanosine, 8-OHdG) tissues were collected at time zero and after 120 days. Results: The data showed that saccharin at 5 mg/kg increased body weight of treated rats after 60 (59%) and 120 (67%) days of treatment. Increased concentration of serum glucose was observed after treatment with saccharin at 5 (75% and 62%) and 10 mg/kg (43% and 40%) following 60 and 120 days, respectively. The concentration of albumin decreased after treatment with saccharin at 2.5 (34% and 36%), 5 (39% and 34%), and 10 mg/kg (15% and 21%) after 60 and 120 days of treatment, respectively. The activity of LDH and uric acid increased proportionally with dosage levels and consumption period. There was an increased concentration of creatinine after treatment with saccharin at 2.5 (125% and 68%), 5 (114% and 45%), and 10 mg/kg (26% and 31%) following 60 and 120 days, respectively. Catalase activity and 8-OHdG increased by 51% and 49%, respectively, following 120 days of treatment with saccharin at 2.5 mg/kg. Elevation in the concentration of isoprostane was observed after treatment with saccharin at all doses. Conclusions: The administration of saccharin throughout the treatment period was correlated with impaired kidney and liver function. Both hyperglycemic and obesity-inducing side effects were observed. There was an increased oxidative status of the liver, as well as exposure to increased oxidative stress demonstrated through the increased levels of isoprostane, uric acid, 8-OHdG, and activity of catalase. Therefore, it is suggested that saccharin is unsafe to be included in the diet.

Effect of Artificial Sweeteners on the Blood Glucose Concentration

Article

Full-text available

Dec 2018

Safety of Food Additives: Sweeteners

Chapter

Jan 2024

Ahmet Dundar

The consumption of harmful substances, including environmental pollutants, endocrine disruptors, and certain food additives, has the potential to compromise food safety and the consumption of safe food, which are fundamental dynamics for society. Furthermore, it can pose a risk to health. This book, entitled Food Safety, aims to assist consumers in developing an awareness of healthy and safe food consumption, beginning with an understanding of the fundamental concepts of food safety, providing e_ective information for the prevention of foodborne diseases, and elucidating the possible e_ects on health. Furthermore, the book addresses contemporary concerns such as food terrorism, packaging safety, and the use of preservatives. Emphasizing food safety from a health perspective, this book is a vital reference for industry professionals, academics, and health professionals. By integrating current research _ndings and real-world examples, the book furnishes readers with a robust foundation of knowledge while raising awareness of food safety. Covering a wide range of food safety issues, this book is a comprehensive resource for anyone working in food toxicology.

Alteration of unfolded protein responses and autophagy signaling represented the molecular basis underlying saccharin toxicity to Drosophila (Diptera: Drosophilidae)

Article

Full-text available

Jul 2021
ARCH INSECT BIOCHEM

The purpose of this study was to develop a new control method for Drosophila using saccharin sodium dihydrate (saccharin), an artificial sweetener that is safe for humans and the environment, and to elucidate its mode of action. In this study, we confirmed that saccharin can dose-dependently inhibit the development of or kill vinegar flies (VFs) and spotted wing Drosophila (SWDs). In addition, we found that low concentrations of saccharin induced a similar effect as starvation in Drosophila, whereas high concentrations of saccharin induced changes in the unfolded protein response (UPR) and autophagy signaling that were unlike starvation and inhibited development or killed the VF and the SWD by performing real-time quantitative polymerase chain reaction analyses. Spinosad is a widely used plant protection agent for SWD control. When saccharin was cotreated with 0.25–1.0 ppm spinosad, an additive insecticidal activity was observed only at high concentrations of saccharin. However, when saccharin was cotreated with 2.0 ppm spinosad, an additive insecticidal activity was observed at low concentrations of saccharin. Taken together, alteration of UPR and autophagy signaling represented the molecular basis underlying saccharin toxicity to Drosophila and concurrent spraying of an insecticide with saccharin could enhance the insecticidal activities. Research Highlights • Saccharin inhibits the development of vinegar fly (VF) and spotted wing Drosophila (SWD) larvae and is toxic to adult Drosophila. • Saccharin induces abnormalities in the autophagy and the unfolded protein response (UPR) signaling of the Drosophila fat body. • The toxicity of saccharin to Drosophila was increased by simultaneous treatment with spinosad.

Bioaccumulation, distribution and retention of 63Ni2+ in the Brown trout (Salmo trutta)

Article

Sep 1988
WATER RES

Brown trout, Salmo trutta, were exposed to water containing 0.1 or 10 μgl−1 of 63Ni2+ for 1 or 3 weeks. Additional trout were exposed to 0.1 or 10 μgl−1 of 63Ni2+ during 3 weeks followed by a 1- or 3-week period without exposure to the metal. At termination of the experimental periods the uptake and distribution of the 63Ni2+ in the fishes were determined by whole-body autoradiography and liquid scintillation spectrometry. The average whole-fish concentration of 63Ni2+ in the fishes was about 3 times higher than the concentration of 63Ni2+ in the water after 1 week's exposure and about 7–8 times higher than in the water after three weeks' exposure. There was no evidence of saturation of the uptake of the 63Ni2+ at 10 μgl−1 as compared to 0.1 μgl−1. The distribution pattern of the 63Ni2+ within the fishes included an accumulation in the blood, the head and trunk kidney, the gills, the connective tissues, the cerebrospinal fluid and the contents of the stomach and the intestines. After 3 weeks without 63Ni2+-exposure the average whole-fish concentrations decreased to about 40% of the levels observed immediately after the 3 week exposure. The amounts of 63Ni2+ in the kidneys in relation to other tissues were higher in the groups of fishes exposed to the 63Ni2+ for 3 weeks followed by the 1- or the 3-week period without 63Ni2+ as compared to the fishes killed immediately after the 3-week 63Ni2+-exposure. The same observation was made for the nervous tissues of the brain and spinal cord, although this uptake in all groups of fishes was rather low. In the gills there was a more rapid decrease in the concentration of 63Ni2+ than the average whole-fish-decrease. Our results show that there is a moderate bioaccumulation of nickel by fishes from the water.

Embryotoxicity and fetal toxicity of nickel in rats

Article

Feb 1978
TOXICOL APPL PHARM

Embryotoxicity and fetal toxicity of nickel chloride (NiCl2) and nickel subsulfide (Ni3S2) were studied in Fischer rats. Injection of NiCl2 (16 mg of Ni/kg, im) on Day 8 of gestation reduced the mean number of liver pups per dam and resulted in diminished body weights of fetuses on Day 20 of gestation and of weanlings at 4 to 8 weeks after birth. Injection of Ni3S2 (80 mg of Ni/kg, im) on Day 6 of gestation reduced the mean number of live pups per dam. No congenital anomalies were found in fetuses from any Ni-treated dams, including dams that received 10 im injections of NiCl2 (2 mg of Ni/kg, twice daily, on Days 6–10 of gestation). 63NiCl2 (12 mg of Ni/kg, im) was administered to a group of nonpregnant female rats and to groups of pregnant rats on Day 8 or 18 of gestation. After 24 hr, the relative concentrations of 63Ni in tissues were: kidney > serum > adrenal ⋍ lung ⋍ ovary > spleen ⋍ heart ⋍ liver > skeletal muscle. Pituitary 63Ni concentrations were much higher in pregnant rats than in nonpregnant females. 63Ni concentrations in products of conception (embryos and embryonic membranes) on Day 9 and in placentas on Day 19 were equivalent to 63Ni concentrations in adrenal, lung, and ovary tissues of the dams. Autoradiography of fetuses and placentas on Day 19 of gestation showed 63Ni localization in fetal urinary bladders and in the basal laminae and yolk sacs of the placentas. These studies show (a) that im injection of NiCl2 and Ni3S2 during early gestation causes embryonic mortality at dosages that do not cause maternal mortality, and (b) that 63Ni(II) can cross the feto-maternal barriers and enter the fetuses during late gestation.

Comparative toxicity studies of chromium-rich welding fumes and chromium on an established human cell line

Article

Jan 1980

Effects of welding fumes in an established human cell line NHIK 3025 have been studied. The welding fume material was collected by air filtration from the welding of stainless steel with a stainless-steel electrode. Addition of the fume particles suspended in 0.9% NaCl to the culture medium reduced cell proliferation and substantially increased the fraction of abnormally large cells. A filtrate of this suspension produced similar effects. Analysis showed that hexavalent chromium constituted 3.5% of the total welding fume material collected. Other metals such as nickel, iron, and manganese were tested at their concentrations in the welding fume particles but displayed only slight toxicity. However, corresponding concentrations of hexavalent chromium alone produced very similar effects of those of the welding fume suspension and filtrate. It is concluded that the toxic effect of the welding fume sample on the bioassay system employed is almost entirely due to hexavalent chromium.

Mutagenicity of nickel sulphate in Drosophila melanogaster

Article

Jul 1986
MUTAT RES-FUND MOL M

Nickel sulphate was injected into Drosophila melanogaster males at different concentrations in order to test the chemical for the induction of SLRL and SCL in germ cells. Nickel sulphate induced SLRL at concentrations tested, with the peak of activity at premeiotic and postmeiotic stages. It failed to produce SCL except at the highest concentration tested, where induction of XO males was significant for the pooled data.

Starting from scratch?: Reinventing the food additive approval process

Article

Apr 1998
BOSTON U LAW REV

Ueber die Oxydation des Orthotoluolsulfamids

Article

Jan 2006
EUR J INORG CHEM

The effect of cyclamate and saccharin on the chromosomes of a Chinese hamster cell line

Article

May 1972
HEREDITAS

Ulf Kristoffersson

Two artificial sweeteners, cyclamate and saccharin, were studied as to their effect on the chromosomes of Chinese hamster cells in vitro. An incidence of chromosome breaks and gaps, significantly increased over the control level, was found in the treated experimental groups. A certain dose relationship of the disturbances induced was indicated. The distribution over the karyotype of the aberrations was nonrandom and the pattern of breaks and gaps in the treated groups coincided largely with that in the controls.

Concept on Sugar- A Review

Article

Sep 2001

Sugars have a long history of safe use in foods. They are common food ingredients that add taste appeal and perform important functions in foods. Besides its pleasant sweetness, sugar performs a host of less obvious and important functions in cooking, baking, candy making and the like. As carbohydrates, sugars are a contributor of calories for the body. The ability to produce solutions of varying degrees of sweetness is important in many food applications, particularly in beverages and confectionery. Low-calorie sweeteners add a taste that is similar to that of sucrose. Intense sweeteners are generally several times sweeter than sucrose. On the other hand, sugar replacers are the bulk and volume providing sweeteners usually less sweet than and different tasting from sugar, commonly used on a one-for-one replacement basis for sugar in recipes. Sugars have been studied extensively for their impact on a variety of issues.

Mutagenicity test with saccharin in the male mouse

Article

Mar 1979
J Environ Pathol Toxicol

The ability of saccharin to induce chromosome aberrations in mammals was tested in male mice injected i.p. with 1, 2, or 4 g saccharin per kg body weight or receiving during a 100 day period 20 g of saccharin per liter of drinking water. Two tests on somatic cells, induction of chromosomal aberrations in bone marrow cells and of micronuclei in polychromatic erythrocytes, and two tests on germ cells, the spermatocyte test on treated males and the dominant lethality test, yielded all negative results. It is concluded that the positive findings reported in the literature were probably due to the mutagenic activity of saccharin impurities.

The metabolism of saccharin in animals

Article

Feb 1975
TOXICOLOGY

Rats given oral doses of [3-14C] saccharin excreted 56-87% of the labeled dose in the urine and 10-40% in the feces during 7 days. Distribution studies showed that the highest levels of 14C were in the kidneys and bladders. The bile was not a significant route of excretion. The presence of labeled CO2 in expired air indicated that saccharin was decarbosylated to a slight degree. DEAE chromatographic separation and isolation of labeled compounds from urine samples showed that more than 99% of the urinary 14C was unchanged saccharin. Up to 1.0% of the 14C was a metabolite identified as 0-sulfamoylbenzoic acid. Comparative metabolic profiles of a dog, rabbit, guinea pig and hamster indicated that there was little difference in the pattern due to animal species or dose level.

A review and biological risk assessment of sodium saccharin

Article

Jul 1992

C I Chappel

Dietary sodium saccharin is associated with bladder tumors when fed at high levels to the male rat. Under these conditions urinary pH, sodium concentration, and volume are elevated and proliferative changes are present in the urothelium. Extensive epidemiological studies have shown that saccharin does not increase the risk of bladder cancer in humans and laboratory investigations have shown that sodium saccharin is not mutagenic and does not bind to DNA. Recent research indicates that the urothelium in male rats is damaged under conditions of high urinary pH and sodium levels by a mechanism that involves alpha 2u-globulin and possibly silicate crystalluria. These studies and their implications for human health risk are reviewed.

Sweeteners, Flavorings, and Dyes in Antibiotic Preparations

Article

Apr 1991

Even though a variety of adverse effects caused by sweeteners, flavorings, and dyes in susceptible individuals have been reported, there is no good single reference with information about these substances in pediatric antimicrobials. Data on sweeteners, flavorings, and dyes in 91 antimicrobial preparations were collected. Sucrose was present in 74 (85%) of 87 preparations, followed by saccharin in 30 (34%) preparations. Mannitol, lactose, and sorbitol were each present in 7 preparations. None of the preparations were free of sweeteners. Thirty-four (37%) of 91 preparations did not specify the flavoring content. While cherry was the most common flavoring used, there were 25 other flavorings. Thirteen different dyes and coloring agents were used in these antimicrobials. Red dye no. 40 was present in 45% of preparations. Tables detailing sweeteners, flavorings, and dyes in different groups of antimicrobials (amoxicillin, ampicillin, cephalosporins, erythromycin, penicillins, sulfonamides, and others) and adverse effects reported with these inert ingredients are presented. These tables should be helpful to physicians in selecting an antimicrobial containing a different sweetener and/or dye when an adverse reaction occurs.

Taste-Induced Changes in Plasma Insulin and Glucose Turnover in Lean and Genetically Obese Rats

Article

Jul 1988
DIABETES

Cephalic-phase insulin release (CPIR) and the changes in glucose turnover induced by saccharin ingestion were studied in freely moving lean and genetically obese fa/fa rats equipped with chronic catheters for blood sampling. Six-hour-fasted lean and obese rats were trained to drink 1 ml sodium saccharin (0.15%) or 1 ml glucose (70%), and blood samples were taken before and after the stimuli. As early as 1-1.5 min poststimulus, there was a significant increase in CPIR in lean and obese rats. The amplitude of the CPIR induced either by saccharin or by glucose in the obese rats was significantly higher than it was in the lean rats. The effect of saccharin ingestion on the hepatic glucose production (HGP) and the rate of glucose disappearance (Rd) was studied in 6-h-fasted lean and obese rats, under non-steady-state conditions, according to a method previously validated. Saccharin ingestion produced a significant increase in HGP and Rd in lean and obese rats compared with basal values. The saccharin-induced increments in HGP and Rd were higher in the obese than in the lean animals. We conclude that saccharin (through taste) appears to elicit parasympathetic (insulin release) and sympathetic (HGP increase) reflexes in lean and obese rats. These taste-induced changes in plasma insulin and glucose turnover are exaggerated in the obese rats and may participate in obesity and in insulin resistance of the overall syndrome.

Clastogenicity in vitro of the Na, K, Ca and Mg salts of saccharin; and of magnesium chloride; consideration of significance

Article

Nov 1986
MUTAT RES-FUND MOL M

The sodium, potassium, calcium and magnesium salts of saccharin, and magnesium chloride, have been shown to be clastogenic to Chinese hamster lung (CHL) fibroblasts in vitro, but only at elevated dose levels (8-16 mg/ml). Saccharin acid was inactive to the limits of its solubility (4 mg/ml). When the data are expressed in terms of ionic concentration, each salt showed a similar clastogenic potency. This suggests that ionic effects induced by these salts in the assay medium may be the critical determinant of the clastogenic effects seen, rather than that the saccharin moiety presents a genotoxic insult to the chromosomes of the cells. The metal-chelating agents EDTA and EGTA were non-clastogenic, but the disodium salt of EDTA showed weak activity prior to toxicity at 0.5 mg/ml. The absence of a clastogenic response for the salts of saccharin at dose levels lower than 4 mg/ml is discussed within the context of the threshold-dependent tumour-promoting activity of high dose levels of sodium saccharin to the bladder of male rats. The doubtful value of conducting in vitro clastogenicity studies at dose levels greater than 10(-2) M is discussed.