Return to Fluorouracil Index Page

Activity: Former insect chemosterilant; now used as a chemotherapeutic drug
Structure:

Adverse Effects:
Note: While this substance was cited as a a former insect chemosterilant, we list a very limited selection of the adverse effects noted in the literature for its use as a chemotherapy drug.

Anemia
Ataxia
Blood
Bone
Brain
Developmental Toxicant
Embryotoxic
Endocrine: Gonadotoxicity / Spermatogenesis
Endocrine: Ovary
Endocrine: Thymus
Gastrointestinal tract
Genotoxic
Heart
Lung
Teratogen
Urinary Tract

Anemia (click on for all fluorinated pesticides)

Major toxic effects result from myelosuppressive action. Clinical effects are leukopenia, thrombocytopenia, and anemia. Loss of hair, occasionally progressing to total alopecia, nail changes, dermatitis, and increased pigmentation and atrophy of skin may occur.
Ref: OXNET profile from Hazardous Substances Data Base for FLUOROURACIL.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm
• Definition for Leukopenia - an abnormal lowering of the white blood cell count

Ataxia (click on for all fluorinated pesticides)

Human Toxicity Excerpts: ... APHTHOUS ULCERATION MAY OCCUR ... OTHER TOXIC EFFECTS INCL ... HYPERPIGMENTATION, PHARYNGITIS, ESOPHAGITIS, CEREBELLAR ATAXIA, & EPISTAXIS. LASSITUDE & ASTHENIA, LASTING FROM 12-36 HR AFTER INJECTION, MAY OCCUR. WHEN ... DEATH /OCCURS/ IT IS USUALLY FROM SEPTICEMIA ... TOPICALLY, /IT/ ... MAY INDUCE PHOTOSENSITIZATION ... . [Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]
Ref: TOXNET profile from Hazardous Substances Data Base. http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

Blood (click on for all fluorinated pesticides)

Major toxic effects result from myelosuppressive action. Clinical effects are leukopenia, thrombocytopenia, and anemia. Loss of hair, occasionally progressing to total alopecia, nail changes, dermatitis, and increased pigmentation and atrophy of skin may occur.
Ref: TOXNET profile from Hazardous Substances Data Base for FLUOROURACIL.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm
• Definitions
Leukopenia - an abnormal lowering of the white blood cell count
Thrombocytopenia - a blood disease characterized by an abnormally small number of platelets in the blood

Bone (click on for all fluorinated pesticides)

-- A major use of fluorouracil is in the palliative treatment of carcinoma of the colon, rectum, breast, stomach, and pancreas that is not amenable to surgery or irradiation. The major toxic effects of fluorouracil are on the normal, rapidly proliferating tissues particularly of the bone marrow and lining of the gastrointestinal tract. Leukopenia, predominantly of the granulocytopenic type, thrombocytopenia, and anemia occur commonly with intravenous fluorouracil therapy at doses ranging from 6 to 12 mg/kg. Pancytopenia and agranulocytosis also have occurred...
-- EPA believes that there is sufficient evidence for listing fluorouracil on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the toxicity of this substance to bone marrow, and on the developmental and chronic neurotoxicity data for this chemical.
Ref: USEPA/OPPT. Support Document for the Health and Ecological Toxicity Review of TRI Expansion Chemicals. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.
• Definition for Leukopenia - an abnormal lowering of the white blood cell count

Potential Adverse Effects on Fetus: Exposure in first trimester: skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus... the incidence of malformations, particularly those affecting the tail, hindlimb bud, and brain, was increased.
Ref: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

Brain (click on for all fluorinated pesticides)

Chronic neurotoxic effects were noted in dogs fed fluorouracil at a dietary dose of 2 mg/kg/day for 6 months. In this study, animals were examined at the end of 3 months and 6 months. At the end of the experiment, or at death, the brain was removed and examined (only one dog survived the entire 6-month period). Histological sections of the brain showed the presence large multiple monolocular vacuoles in the wall of the fornix of the third ventricle.
Ref: USEPA/OPPT. Support Document for the Health and Ecological Toxicity Review of TRI Expansion Chemicals. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

-- Absorption, Distribution & Excretion : Fluorouracil is distributed into tumors, intestinal mucosa, bone marrow, liver, and other tissues. Despite its limited lipid solubility, the drug readily crosses the blood-brain barrier and distributes into CSF and brain tissue... [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993).
-- Potential Adverse Effects on Fetus: Exposure in first trimester: skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus... the incidence of malformations, particularly those affecting the tail, hindlimb bud, and brain, was increased.
Ref: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

-- PubMed abstract: Two metabolites of 5-fluorouracil (FU), monofluoroacetic acid (FA) and alpha-fluoro-beta-alanine (FBAL), were continuously administered into the left ventricle of the brain in cats for up to 1 month to investigate the mechanism of neurotoxicity of FU and its derivatives. The cumulative doses of FU and FBAL over a 1-month period were 1.5-45 mg (20 cats) and 0.2-4.8 mg (21 cats), respectively. As controls for each experimental group, acetic acid (AA) and beta-alanine (BAL) were administered. In terms of survival time in relation to the cumulative dose and molecular weight, FBAL was more toxic than FA. Neuropathologically, two types of change, vacuoles and necrosis/softening-like change, were found. The vacuoles were 20-50 microns in diameter, and distributed mainly in the cerebellar nuclei, white matter and the tectum and tegmentum of the brain stem in both experimental groups. Electron microscopically, these vacuoles were due to splitting of the myelin intraperiod line or separation between the axon and the innermost layer of myelin. Necrosis/softening-like change occurred preferentially in the FBAL group and was located symmetrically in the superior and inferior colliculi, oculomotor nuclei and thalamus. Both types of neuropathological change, especially those in the FBAL group, were similar to those found in cats orally administered with FU and its derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)
Ref: Acta Neuropathol (Berl) 1990;81(1):66-73; Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and alpha-fluoro-beta-alanine; Okeda R, Shibutani M, Matsuo T, Kuroiwa T, Shimokawa R, Tajima T.

Developmental toxicant (click on for all fluorinated pesticides)

Developmental abnormalities or other effects on newborns were reported in offspring of women receiving 150 or 240 mg/kg fluorouracil intravenously during weeks 11 to 14 or 20 to 31 of pregnancy. In addition, maternal toxicity to the reproductive organs, toxicity to the fetus, and developmental abnormalities have been reported in mice, rats, and hamsters receiving oral, intraperitoneal, or intramuscular doses of fluorouracil ranging from 10 to 700 mg/kg.
Ref: USEPA/OPPT. Support Document for the Health and Ecological Toxicity Review of TRI Expansion Chemicals. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

Abstract: Biologically based dose-response (BBDR) models are a way to incorporate mechanistic information into dose-response assessment. The chemotherapeutic drug 5-fluorouracil (5-FU) has been used as a prototypic compound for the construction of a BBDR model for developmental toxicity (Shuey et al. 1994). Previous work (Lau et al. 2000) has provided data and a general mechanistic framework for the development toxicity of 5-FU when it was administered to pregnant rats subcutaneously on gestation day 14. Here we develop a mathematical model relating maternally administered dose to embryonal thymidylate synthetase (TS) inhibition, and thymidylate synthetase inhibition to various measures of deoxyribonucleotide (dNTP) pool perturbation, and estimate parameters and the uncertainty of subsequent predictions using the previously collected data. The strategy used was to develop semi-empirical submodels for 5-FU pharmacokinetics, 5-FU metabolism and TS inhibition, and nucleotide pool perturbation, and to estimate model parameters from the dose-response data described in Lau et al. (2000). Even for the relatively simple models described here, not all parameters could be uniquely estimated using data from dose-response and time-course studies, and some values had to be assigned based on plausible guesses. The models developed predict that even minimal doses of 5-FU should result in some perturbation of dNTP pools. In particular, the relationship between dNTP pool perturbation and fetal weight deficit suggests that if there is a biological threshold for the effect of 5-FU on fetal weight, the responsible repair or compensation mechanism must be downstream of dNTP pool perturbation, and saturable at 5-FU doses lower than 10 mg/kg, the lowest dose examined for developmental effects in these studies.
Ref: Setzer RW et al. (2001). Creating a biologically-based dose-response model for developmental toxicity of 5-fluorouracil in the rat. Toxicologist 2001 Mar;60(1):145. As cited on Toxnet.

Embryotoxic (click on for all fluorinated pesticides)

Abstract: The chemotherapeutic agent 5-fluorouracil (5-FU) is a known developmental toxicant in the rat both in vivo and in vitro. The mechanism of the drug's embryotoxic effect is unclear, but it has been postulated that 5-FU inhibits thymidylate synthase activity, leading to a deficiency of thymidine and a decrease in DNA synthesis. If this is the case, addition of excess exogenous thymidine should reverse the drug's embryotoxicity. Rat embryos were cultured beginning on day 10 of gestation (for 48 hours) in a whole embryo culture system. For the initial three hours of the culture period, 5-FU was present at a final concentration of 3 ug/mL. Following removal of 5-FU, various concentrations of thymidine were added for the remainder of the culture period. Treatment with 5-FU decreased the morphological score, number of somite pairs, crown-rump and head lengths, as well as DNA and protein contents; the incidence of malformations, particularly those affecting the tail, hindlimb bud, and brain, was increased. With addition of thymidine, there was attenuation of all parameters examined and fewer malformations. Exogenous thymidine was not able to reverse the effects of 5-FU completely, even if it was present for the entire 48 hour culture period, including the three hour 5-FU treatment phase. These results suggest that 5-FU may induce a thymidine deficiency in treated rat embryos, but some other effect(s) also appear to be involved in the embryotoxicity induced by the drug.
Ref: Hansen DK et al. (1988-89). Attenuation of 5-fluorouracil-induced embryotoxicity by exogenous thymidine in vitro. Attenuation of 5-fluorouracil-induced embryotoxicity by exogenous thymidine in vitro. As cited on Toxnet.

Abstract: 5-Fluorouracil (5-FU) is a widely used antitumor agent that is embryotoxic in rats at maternal therapeutic levels. A biologically based dose-response model (BBDR) was developed that relates a single dose of 5-FU on gestation day 14 in rats to cell cycle effects in developing fetuses, specifically the inhibition of thymidylate synthetase (TS; due to formation of a FdUMP/TS/folate complex) with subsequent reduction in thymidylate (dTMP) levels, thymidine-5'-triphosphate (dTTP; a DNA precursor) and, ultimately, disruption of DNA synthesis. The initial modeling of the pharmacokinetic component of the BBDR model was based upon a two-compartment PBPK model (Collins et al., 1980) for the maternal kinetics with an added compartment for the fetal kinetics of 5-FU. This BBDR model described well the 5-FU concentration data from gestation day 19, but fetal compartment concentrations on day 14 and the time course of the inhibition were modeled empirically rather than mechanistically. To incorporate more physiological information, a pregnant rat PBPK model developed by O'Flaherty et al. (TAP 112:245-256, 1992) for the weak acid dimethyloxazolidine-2,4-dione (DM0) was adapted for use in the 5-FU BBDR model. The O'Flaherty model adjusts for changes in the dam and fetal body weights, blood flows, and organ volumes as the gestation progresses. Metabolism of 5-FU and tissue partitioning was also added to the model. Sensitivity analysis and use of different data sets as the basis for parameter estimates in this more detailed PBPK component provided insights into the importance of 5-FU pharmacokinetics to the resulting changes in thymidylate synthesis compared with other potential pharmacodynamic interactions.
Ref: Setzer RW et al. (2000). Incorporating a validated PBPK pregnant rat model into a BBDR model for the embryotoxicity of 5-fluorouracil. Toxicologist 2000 Mar;54(1):93. As cited on Toxnet.

Endocrine: Ovary (click on for all fluorinated pesticides)

Fluorouracil has not been adequately studied in animals to determine its effects on fertility and general reproductive performance. Following intraperitoneal administration of 125 or 250 mg/kg in rats, chromosomal aberrations and changes in chromosomal organization of spermatogonia were induced; spermatogonial differentiation was also inhibited, resulting in transient infertility. In a strain of mouse that is sensitive to the induction of sperm head abnormalities after exposure to a number of chemical mutagens and carcinogens, no abnormalities were produced at oral dosages of up to 80 mg/kg daily. Following intraperitoneal administration at weekly doses of 25 or 50 mg/kg weekly for 3 weeks during the preovulatory phases of oogenesis in female rat, the incidence of fertile matings was substantially reduced, development of preimplantation and postimplantation embryos was delayed, and the incidence of preimplantation lethality and chromosomal anomalies in the embryos was increased. In a limited study in rabbits, a single 25 mg/kg dose or daily doses of 5 mg/kg for 5 days had no effect on ovulation, appeared not to affect implantation, and had only a limited effect in producing zygote destruction. Drugs that inhibit DNA, RNA, and protein synthesis like fluorouracil might be expected to have adverse effects on gametogenesis. [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]
Ref: TOXNET profile from Hazardous Substances Data Base for FLUOROURACIL.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm
• Definitions:
Gametogenesis: The meiotic process by which mature gametes (ova and sperm) are formed.
Oogenesis refers specifically to the production of ova and spermatogenesis to the production of sperm. [ Definition from: GeneTests from the University of Washington and Children's Health System, Seattle]

Endocrine: Testes and Spermatogenesis (click on for all fluorinated pesticides)

Fluorouracil has not been adequately studied in animals to determine its effects on fertility and general reproductive performance. Following intraperitoneal administration of 125 or 250 mg/kg in rats, chromosomal aberrations and changes in chromosomal organization of spermatogonia were induced; spermatogonial differentiation was also inhibited, resulting in transient infertility. In a strain of mouse that is sensitive to the induction of sperm head abnormalities after exposure to a number of chemical mutagens and carcinogens, no abnormalities were produced at oral dosages of up to 80 mg/kg daily. Following intraperitoneal administration at weekly doses of 25 or 50 mg/kg weekly for 3 weeks during the preovulatory phases of oogenesis in female rat, the incidence of fertile matings was substantially reduced, development of preimplantation and postimplantation embryos was delayed, and the incidence of preimplantation lethality and chromosomal anomalies in the embryos was increased. In a limited study in rabbits, a single 25 mg/kg dose or daily doses of 5 mg/kg for 5 days had no effect on ovulation, appeared not to affect implantation, and had only a limited effect in producing zygote destruction. Drugs that inhibit DNA, RNA, and protein synthesis like fluorouracil might be expected to have adverse effects on gametogenesis. [McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]
Ref: TOXNET profile from Hazardous Substances Data Base for FLUOROURACIL.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm
• Definitions
Gametogenesis: The meiotic process by which mature gametes (ova and sperm) are formed.
Oogenesis refers specifically to the production of ova and spermatogenesis to the production of sperm. [ Definition from: GeneTests from the University of Washington and Children's Health System, Seattle]

Abstract: Introduction: Anticancer drugs have variable effects on male gonadal function. There were many reports regarding gonadotoxicity induced by drugs like vinblastine, procarbazine and methotrexate. However, literature of 5-fluorouracil induced gonadotoxicity appears to be lacking. The present study investigates the sperm shape anomalies induced by 5-fluorouracil at various doses on Swiss albino mice. Methods: Mice were treated with therapeutic (12 mg/kg body weight) and high dose (24 mg/kg body weight) of 5-fluorouracil for 5 consecutive days. Mice were sacrificed on 35th day after the first injection. Epididymis were minced with normal saline and stained with eosin. One thousand sperms/animal were counted including the control groups. Normal and abnormal sperms were recorded. Results: A mean abnormality of 13.26% at therapeutic dose and 8.76% at high dose was observed. Conclusion: 5-fluorouracil was found to be gonadotoxic to mice which is directly proportional to the dosage. Hence care must be taken before commencing 5-fluorouracil therapy.
Ref: D'Souza AS (2001). 5-Fluorouracil induced sperm shape anomalies in Swiss albino mice. Indian J Pharmacol Aug;33(4):308. As cited on Toxnet.

Endocrine: Thymus (click on for all fluorinated pesticides)

POTENTIAL ADVERSE EFFECTS ON FETUS: Exposure in first trimester resulted in skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus.
Ref: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

Gastrointestinal tract (click on for all fluorinated pesticides)

A major use of fluorouracil is in the palliative treatment of carcinoma of the colon, rectum, breast, stomach, and pancreas that is not amenable to surgery or irradiation. The major toxic effects of fluorouracil are on the normal, rapidly proliferating tissues particularly of the bone marrow and lining of the gastrointestinal tract. Leukopenia, predominantly of the granulocytopenic type, thrombocytopenia, and anemia occur commonly with intravenous fluorouracil therapy at doses ranging from 6 to 12 mg/kg. Pancytopenia and agranulocytosis also have occurred.
Ref: USEPA/OPPT. Support Document for the Health and Ecological Toxicity Review of TRI Expansion Chemicals. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

POTENTIAL ADVERSE EFFECTS ON FETUS: Exposure in first trimester resulted in skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus.
Ref: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

Genotoxic (click on for all fluorinated pesticides)

Ref: Gene-Tox from Toxnet.
GENE-TOX Evaluation B (post-1980):

GENE-TOX Evaluation A (pre-1980):

Species/Cell Type:	Mouse (C3H/10T1/2) cells
Assay Type:	Cell transformation
Assay Code:	CTH+
Results:	Positive
Panel Report:	EMICBACK/50076; MUTAT RES 114:283-385,1983

Species/Cell Type:	Mammalian polychromatic erythrocytes
Assay Type:	Micronucleus test, chromosome aberrations
Assay Code:	MNT+
Results:	Positive
Panel Report:	EMICBACK/50890; MUTAT RES 123:61-118,1983

Species/Cell Type:	Tradescantia species
Assay Type:	Chromosome aberrations
Assay Code:	TRC+D
Results:	Positive
Dose Response:	With dose response
Panel Report:	EMICBACK/48094; MUTAT RES 99:293-302,1982

Heart (click on for all fluorinated pesticides)

POTENTIAL ADVERSE EFFECTS ON FETUS: Exposure in first trimester resulted in skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus.
Ref: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

Lung (click on for all fluorinated pesticides)

POTENTIAL ADVERSE EFFECTS ON FETUS: Exposure in first trimester resulted in skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus.
Ref: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

Teratogenic (click on for all fluorinated pesticides)

REPRODUCTIVE HAZARDS. Fluorouracil is known to be teratogenic in animals, as well as causing degenerative effects in male test animals' reproductive system.
Ref: TOXNET profile from Hazardous Substances Data Base for Fluorouracil.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm

Urinary Tract (click on for all fluorinated pesticides)

POTENTIAL ADVERSE EFFECTS ON FETUS: Exposure in first trimester resulted in skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus.
Ref: TOXNET profile from Hazardous Substances Data Base.
http://www.fluoridealert.org/pesticides/Fluorouracil.TOXNET.HSDB.htm