Spermicide used alone for contraception.

BACKGROUND: Spermicides have been used as contraceptives for thousands of years. Despite this long use, only recently have studies examined the comparative efficacy and acceptability of these vaginal medications. Spermicides contain an active ingredient (most commonly nonoxynol-9) and a formulation used to disperse the product, such as foam or vaginal suppository. OBJECTIVES: This review examined all known randomized controlled trials of a spermicide used alone for contraception. SEARCH STRATEGY: We searched the following computerized databases from inception to July 2004 for randomized controlled trials of spermicides for contraception: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, POPLINE, LILACS, and EMBASE. We examined the reference list of each trial found as well as that of review articles and textbook chapters. SELECTION CRITERIA: We included any trial of a commercial product used alone for contraception. Each included trial must have provided sufficient information to determine pregnancy rates. We located reports from 14 trials. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted information from the trials identified. We did not conduct a meta-analysis, since most trials had large losses to follow-up. We entered the data into tables and presented the results descriptively. MAIN RESULTS: In the largest trial to date, the gel (Advantage S) containing the lowest dose of nonoxynol-9 (52.5 mg) was significantly less effective in preventing pregnancy than were gels with higher doses of the same agent (100 mg and 150 mg). Probabilities of pregnancy by six months were 22% for the 52.5 mg gel, 16% for the 100 mg dose, and 14% for the 150 mg dose. In the same trial, the three different vehicles with 100 mg of nonoxynol-9 had similar efficacy. Interpretation of these figures is limited, since 39% of participants discontinued the method or were lost from the trial. Few important differences in efficacy emerged in other trials. AUTHORS' CONCLUSIONS: The probability of pregnancy varied widely in reported trials. A gel containing nonoxynol-9 52.5 mg was inferior to two other products tested in the largest trial. Aside from this finding, personal characteristics and behavior of users may be more important than characteristics of the spermicide products in determining the probability of pregnancy. Gel was liked more than the film or vaginal suppository in the largest trial. Spermicide trials have the dual challenges of difficult recruitment and high discontinuation rates; the latter threatens trial validity.

Emergency contraception.

Emergency contraceptives are methods that prevent pregnancy when used shortly after unprotected sex. Three different emergency contraceptive methods are safe, simple, and widely available in the United States. These are: (1) ordinary combined oral contraceptives containing ethinyl estradiol and levonorgestrel taken in a higher dose for a short period of time and started within a few days after unprotected intercourse; (2) levonorgestrel-only tablets used similarly; and (3) copper-bearing intrauterine devices inserted within approximately 1 week after unprotected intercourse. Emergency contraceptive use is best known for women who have been raped, but the methods are also appropriate for women who have experienced condom breaks, women who did not use any method because they were not planning on having sex, or women who had unprotected intercourse for any other reason. Unfortunately, few women know about emergency contraceptives, and few clinicians think to inform their patients routinely about the option. A nationwide toll-free hotline (1-888-NOT-2-LATE) and a website (http://not-2-late.com) can help women learn about these options. Sharing "family planning's best-kept secret" widely with women could prevent as many as a million unwanted pregnancies annually in the United States.

On the mechanisms of action of short-term levonorgestrel administration in emergency contraception.

The effects of short-term administration of levonorgestrel (LNG) at different stages of the ovarian cycle on the pituitary-ovarian axis, corpus luteum function, and endometrium were investigated. Forty-five surgically sterilized women were studied during two menstrual cycles. In the second cycle, each women received two doses of 0.75 mg LNG taken 12 h apart on day 10 of the cycle (Group A), at the time of serum luteinizing hormone (LH) surge (Group B), 48 h after positive detection of urinary LH (Group C), or late follicular phase (Group D). In both cycles, transvaginal ultrasound and serum LH were performed from the detection of urinary LH until ovulation. Serum estradiol (E2) and progesterone (P(4)) were measured during the complete luteal phase. In addition, an endometrial biopsy was taken at day LH + 9. Eighty percent of participants in Group A were anovulatory, the remaining (three participants) presented significant shortness of the luteal phase with notably lower luteal P4 serum concentrations. In Groups B and C, no significant differences on either cycle length or luteal P4 and E2 serum concentrations were observed between the untreated and treated cycles. Participants in Group D had normal cycle length but significantly lower luteal P4 serum concentrations. Endometrial histology was normal in all ovulatory-treated cycles. It is suggested that interference of LNG with the mechanisms initiating the LH preovulatory surge depends on the stage of follicle development. Thus, anovulation results from disrupting the normal development and/or the hormonal activity of the growing follicle only when LNG is given preovulatory. In addition, peri- and post-ovulatory administration of LNG did not impair corpus luteum function or endometrial morphology.

Emergency contraception over-the-counter: the medical and legal imperatives.

Requiring a physician's prescription for hormonal emergency contraceptive pills makes no sense. Unintended pregnancies remain endemic in the United States, and wider use of emergency contraceptive pills could substantially help. However, the prescription requirement poses an unnecessary barrier to prompt, effective use of this preventive therapy. According to the Durham-Humphrey Amendment of 1951, the default option for all new drugs is, in principle, over-the-counter, unless a drug is addictive or dangerous when self-administered. Clearly, hormonal emergency contraception is neither of these. Emergency contraceptive pills meet all the customary criteria for over-the-counter use: low toxicity, no potential for overdose or addiction, no teratogenicity, no need for medical screening, self-identification of the need, uniform dosage, and no important drug interactions. The Food and Drug Administration is authorized, and, by its own regulations, should be required to switch hormonal emergency contraception to over-the-counter status without delay. The current prescription requirement is not only gratuitous but also harmful to women's health because it impedes access to this important therapy.

Effect of the Yuzpe regimen of emergency contraception on markers of endometrial receptivity.

This exploratory study was designed to determine whether treatment with the Yuzpe regimen of emergency contraception altered endometrial integrin expression or other markers of uterine receptivity. Nineteen parous women were followed for two menstrual cycles. In the second cycle, each participant took 100 mg ethinyl oestradiol and 1 mg norgestrel on the day of the urinary luteinizing hormone (LH) surge and repeated the dose 12 h later. In both cycles, endometrial biopsy, phlebotomy and vaginal sonogram were performed 8-10 days after the urinary LH surge. No significant difference was found between untreated and treated cycles in most measures of endometrial histology or in endometrial expression of beta3 integrin subunit, leukaemia inhibitory factor, glycodelin, or progesterone receptors assessed by immunohistochemical techniques. Five statistically significant changes were noted in treated cycles: a reduction in endometrial MUC-1 expression, an increase in endometrial oestrogen receptor, lower luteal phase serum oestrogen concentration, reduced endometrial thickness, and greater proportion of glandular supranuclear vacuoles. The relationship of these findings to the contraceptive action of the Yuzpe regimen is unclear.

Meclizine for prevention of nausea associated with use of emergency contraceptive pills: a randomized trial.

OBJECTIVE: We conducted a randomized trial to determine whether pretreatment with meclizine reduces the incidence of nausea and vomiting associated with the Yuzpe regimen of emergency contraception. METHODS: We randomly assigned 343 women aged 18-45 years who were not at risk for pregnancy to pretreatment with 50 mg of meclizine, placebo, or no drug 1 hour before the first of two doses of emergency contraceptive pills. We asked participants to complete three questionnaires over the following 48 hours. RESULTS: The incidence of nausea was 47% in the group pretreated with meclizine and 64% in the other two groups (relative risk adjusted for center 0.7, 95% confidence intervals 0.6, 0.9 for comparisons of meclizine with both placebo and no drug). The severity of nausea and the incidence of vomiting were also significantly lower in the meclizine pretreatment group than in the other two groups. Drowsiness was reported by about twice as many women in the meclizine pretreatment group (31%) than in the other two groups (13% in the placebo group, 16% in the no-pretreatment group; P < .01 for both comparisons). CONCLUSION: Meclizine is effective for preventing nausea and vomiting associated with the Yuzpe regimen of emergency contraceptive pills. Women using this drug should be cautioned to anticipate drowsiness.

Bundling a pregnancy test with the Yuzpe regimen of emergency contraception.

The recent United States Food and Drug Administration approval of a commercial kit containing the Yuzpe regimen for emergency contraception is a welcome event. Unlike emergency contraceptive pills sold in other countries, however, the United States product has a pregnancy test bundled with the pills. The test could identify existing pregnancies and avoid unnecessary use of the pills, although any protection against lawsuits alleging injury to an embryo is speculative. Conversely, no major medical organization recommends routine pregnancy testing before using emergency contraceptive pills. The test might stigmatize the Yuzpe regimen as being dangerous to an embryo. Difficulty in understanding the pregnancy test instructions could, paradoxically, deter some women from using the pills after having bought them. The bulky size of the pregnancy test reagent stick makes the package indiscreet, and the test adds unnecessary cost to emergency contraception. The greatest usefulness of the test could be to confirm or exclude a pregnancy several weeks after taking the pills, rather than before. If bundling an unnecessary test with emergency contraception is the only way to bring this useful product to the United States market, then the public health benefits could outweigh the disadvantages. However, this approach sets a worrisome precedent and further isolates the United States from the international medical community.

Intrauterine devices. The optimal long-term contraceptive method?

OBJECTIVE: To review selected data on the effectiveness, safety, cost and technical ease of intrauterine device (IUD) use compared with Norplant and surgical sterilization. STUDY DESIGN: Literature review. RESULTS: IUDs are highly effective, safe and relatively inexpensive methods of contraception that may offer advantages for some women over other long-term methods, such as sterilization and Norplant. IUDs provide protection against pregnancy comparable to that provided by female sterilization, and they may be more effective than Norplant. IUDs have a long duration of effectiveness: the copper T 380A (TCu380A) is effective for at least 10 years, and the levonorgestrel (LNg) IUD appears to be effective for at least 7. Norplant is effective for only five years. Both types of IUD can disrupt menstrual bleeding patterns, although the patterns of bleeding are different. Copper IUDs often increase blood loss, whereas the LNg IUD, like Norplant, substantially reduces menstrual bleeding. The most important adverse outcome associated with IUD use is higher rates of pelvic inflammatory disease; careful attention to proper insertion techniques can reduce this risk substantially, and LNg IUDs may cause no increase in risk. IUDs, like both sterilization and Norplant, provide no protection against sexually transmitted disease. The TCu380A IUD is extremely cost-effective. There is as yet no public sector price for the LNg IUD, which has not been approved by the U.S. Food and Drug Administration and is not provided by family planning donor organizations. If it can be made available to the public sector at a price substantially less than its present market price, the LNg IUD would be a useful addition to the contraceptive armamentarium for developing countries. CONCLUSION: Providers, consumers and family planning program managers should begin to see IUDs as potential substitutes for both surgical sterilization and Norplant.

PIP: This study reviews literatures on the effectiveness, safety, cost and technical ease of IUD use as compared with Norplant and surgical sterilization. Findings revealed that IUDs are highly effective, safe and relatively inexpensive methods of contraception that may offer advantages for some women over other long-term methods, such as sterilization and Norplant. IUDs provide protection against pregnancy comparable to that provided by female sterilization, and they may be more effective than Norplant. IUDs have a long duration of effectiveness: the copper T 380A is effective for at least 10 years, and the levonorgestrel (LNG) IUD seems to be effective for at least 7 years. Norplant is effective for only 5 years. Both types of IUD can disturb menstrual bleeding patterns, although the patterns of bleeding are different. Copper IUDs often increase blood loss, whereas the LNG IUD, like Norplant, substantially reduces menstrual bleeding. The most important adverse outcome associated with IUD use is higher rates of pelvic inflammatory disease; careful attention to proper insertion techniques can reduce this risk substantially, and LNG IUDs may cause no increase in risk. IUDs, like both sterilization and Norplant, provide no protection against sexually transmitted diseases.

Statistical evidence about the mechanism of action of the Yuzpe regimen of emergency contraception.

OBJECTIVE: To determine whether published statistical evidence about the effectiveness of the Yuzpe regimen of emergency contraception provides insight about its mechanism of action. DATA SOURCES: We searched the literature for studies that present information on the effectiveness of the Yuzpe regimen, on the probability of conception by menstrual cycle day, or on the occurrence of ovulation in women treated with the regimen. Searches of the electronic databases MEDLINE, POPLINE, EMBASE, and BIOSIS were supplemented by scrutiny of the bibliographies of all papers identified through the electronic search. METHODS OF STUDY SELECTION: We identified a review of the effectiveness of the Yuzpe regimen based on all seven clinical trials that present the number of women treated on each cycle day and the outcome of each treatment; this review also provided external estimates of the probability of conception by cycle day of unprotected intercourse from two other clinical studies. We identified three clinical studies of ovulation after treatment with the Yuzpe regimen. We included all identified studies in our analysis. TABULATION, INTEGRATION, AND RESULTS: We compared 40 estimates of the actual effectiveness of the Yuzpe regimen with the maximum theoretical effectiveness that could be obtained if the regimen worked only by preventing or delaying ovulation. In the overwhelming majority of these comparisons, the former exceeded the latter. CONCLUSION: The Yuzpe regimen could not be as effective as it appears to be if it worked only by preventing or delaying ovulation.

Trial of calcium to prevent preeclampsia.

BACKGROUND: Previous trials have suggested that calcium supplementation during pregnancy may reduce the risk of preeclampsia. However, differences in study design and a low dietary calcium intake in the populations studied limit acceptance of the data. METHODS: We randomly assigned 4589 healthy nulliparous women who were 13 to 21 weeks pregnant to receive daily treatment with either 2 g of elemental calcium or placebo for the remainder of their pregnancies. Surveillance for preeclampsia was conducted by personnel unaware of treatment-group assignments, using standardized measurements of blood pressure and urinary protein excretion at uniformly scheduled prenatal visits, protocols for monitoring these measurements during the hospitalization for delivery, and reviews of medical records of unscheduled outpatient visits and all hospitalizations. RESULTS: Calcium supplementation did not significantly reduce the incidence or severity of preeclampsia or delay its onset. Preeclampsia occurred in 158 of the 2295 women in the calcium group (6.9 percent) and 168 of the 2294 women in the placebo group (7.3 percent) (relative risk, 0.94; 95 percent confidence interval, 0.76 to 1.16). There were no significant differences between the two groups in the prevalence of pregnancy-associated hypertension without preeclampsia (15.3 percent vs. 17.3 percent) or of all hypertensive disorders (22.2 percent vs. 24.6 percent). The mean systolic and diastolic blood pressures during pregnancy were similar in both groups. Calcium did not reduce the numbers of preterm deliveries, small-for-gestational-age births, or fetal and neonatal deaths; nor did it increase urolithiasis during pregnancy. CONCLUSIONS: Calcium supplementation during pregnancy did not prevent preeclampsia, pregnancy-associated hypertension, or adverse perinatal outcomes in healthy nulliparous women.

Contraceptive efficacy, pharmacokinetics, and safety of Annuelle biodegradable norethindrone pellet implants.

OBJECTIVE: To evaluate the contraceptive efficacy, pharmacokinetics, and safety of two formulations of Annuelle (Endocon, Inc., South Walpole, MA) biodegradable norethindrone (NET) SC pellet implants. DESIGN: Prospective observational study. SETTING: Two clinical sites in the United States. PATIENT(S): Thirty-nine healthy, fertile, sexually active women. INTERVENTION(S): Nineteen women received a four-pellet system containing 174 mg NET; 20 women received a five-pellet system containing 266.5 mg NET. MAIN OUTCOME MEASURE(S): Contraceptive efficacy, median serum NET levels, adverse events. RESULT(S): No pregnancies were observed in 293 woman-months in the four-pellet group or in 375 woman-months in the five-pellet group. An initial burst in median serum NET levels occurred in the first 24 hours postinsertion followed by a steady decline over the next 3 years. Norethindrone levels varied considerably among women. The main side effect was bleeding abnormalities, which persisted in half the participants for up to 2 years. No serious adverse events were reported that were related to the pellets. Pellet insertion and removal generally were uncomplicated. CONCLUSION(S): Annuelle shows potential as an effective, safe contraceptive with distinct advantages over other long-acting agents, because it is biodegradable but can be removed if problems arise or if fertility is desired.

PIP: The contraceptive efficacy, pharmacokinetics, bleeding profiles, and safety of two formulations of the Annuelle contraceptive implant system were investigated in a prospective study conducted at two clinical sites in the US. 19 women received a four-pellet system containing 174 mg of norethindrone (NET) and 20 women received a five-pellet system containing 266.5 mg of NET. Participants were followed quarterly for up to 39 months. No pregnancies were recorded during 293 woman-months in the four-pellet group and 375 woman-months in the five-pellet group. Most women exhibited a burst in NET levels (values equal to or exceeding 2 ng/ml) 24 hours after pellet insertion, followed by a steady decline over the next 3 years. Ovulation was inhibited in most participants in both groups at 9 months after insertion, and this protective effect persisted as long as 2 years in 16 of the 39 subjects. More than 80% of women in both groups had at least one clinically important bleeding pattern (e.g., frequent, irregular, or prolonged bleeding) in the first 90-day interval; this percentage dropped over time, but persisted in half the participants for up to 2 years. Serum levels of total cholesterol, low density lipoproteins, and triglycerides dropped substantially after pellet insertion in both groups, while high density lipoprotein levels remained fairly constant. Overall, the Annuelle system is considered to have potential as a safe, long-acting contraceptive agent capable of being surgically removed before complete absorption. Of concern, however, is the relatively long period during which the product releases detectable amounts of NET but may no longer be a fully effective contraceptive agent.

Relation between sodium balance and menstrual cycle symptoms in normal women.

OBJECTIVE: To determine whether sodium balance affects expression of menstrual symptoms. DESIGN: Prospective study of menstrual symptoms during three cycles: a baseline month (usual intake of sodium, 115 mmol/d) followed by 2 months of sodium restriction (intake of sodium, 73.0 mmol/d). Added salt was allowed during the last month. Investigators were aware of the diet sequence. SETTING: Outpatient. Meals were prepared by a metabolic kitchen during the 2 months that the participants received salt-restricted diets. PARTICIPANTS: 13 healthy menstruant women. MEASUREMENTS: Plasma sodium levels, urinary sodium excretion, and plasma renin activity were measured for five time periods during the baseline cycle and the two cycles of salt-restricted diet. Eleven women completed a questionnaire assessing somatic symptoms and sensory cravings at the same time every day during the 3-month study period. RESULTS: Sodium restriction was associated with a mean decrease (+/- one half of the 95% CI) in plasma sodium levels of 0.9 +/- 0.9 mmol/L from a mean of 139.3 mmol/L during the baseline cycle (P = 0.018), a decrease in urinary sodium excretion of 40.3 +/- 18 mmol/d from a mean of 117 mmol/d during the baseline cycle (P = 0.001), and an increase in plasma renin activity of 0.14 +/- 0.08 ng/(L . s) from a mean of 0.28 ng/(L . s) during the baseline cycle (P = 0.008). During the luteal phase of the sodium restriction cycle, significant decreases in plasma sodium levels of 1.23 +/- 0.5 mmol/L (from values of 138.8 mmol/L during the follicular phase) and increases in urinary sodium excretion of 27.2 +/- 10 mmol/d (from values of 65.5 mmol/d during the follicular phase) preceded periods when menstrual symptoms were most severe. Ratings of breast tenderness increased sixfold to eightfold in the late luteal phase (P < 0.001) and those of swelling or bloating increased twofold to threefold during early menses (P < 0.001) compared with nadir symptom ratings during each cycle. Sodium cravings increased in the luteal phase of all cycles but were not accompanied by increased sodium intake when access to added salt was allowed. CONCLUSIONS: Breast tenderness and bloating did not result from sodium retention in the luteal phase of the menstrual cycle. During normal and sodium-restricted diet cycles, women actually had urinary sodium loss, not retention, during the luteal phase; severity of menstrual symptoms was unchanged.

Trial of Calcium for Preeclampsia Prevention (CPEP): rationale, design, and methods.

The results of ten clinical trials suggest that supplemental calcium may prevent preeclampsia. However, methodologic problems and differences in study design limit the acceptance of the results and their relevance to other patient populations. Many of the trials were conducted in countries where, unlike the United States, the usual daily diet contained little calcium. Moreover, none of the trials has reported the outcome of systematic surveillance for urolithiasis, a potential complication of calcium supplementation. In response to the need for a thorough evaluation of the effects of calcium supplementation for the prevention of preeclampsia in the United States, the trial of Calcium for Preeclampsia Prevention (CPEP) was undertaken at five university medical centers. Healthy nulliparous patients were randomly assigned to receive either 2 g supplemental calcium daily (n = 2295) or placebo (n = 2294) in a double-blind study. Study tablets were administered beginning from 13 to 21 completed weeks of gestation and continued until the termination of pregnancy. CPEP employed detailed diagnostic criteria, standardized techniques of measurement, and systematic surveillance for the major study endpoints and for urolithiasis. The nutrient intake of each patient was assessed at randomization and at 32-33 weeks gestation. This report describes the study rationale, design, and methods.

Development of a practical screening tool to identify preterm, low-birthweight neonates in Ethiopia.

Preterm, low-birthweight (LBW) newborn infants are at high risk of neonatal mortality and morbidity and need early referral for special paediatric care. In developing countries, birthweight and gestational age often cannot be measured and a practical screening tool based on surrogate neonatal body measurements to identify high-risk infants would be very useful. We studied a consecutive series of 843 singleton infants born at a referral hospital in Addis Ababa, Ethiopia. Gestational age, birthweight, and four body measurements (chest, head, and mid-arm circumferences and length) were accurately recorded. We randomly divided the series into equal-sized training and validation groups. In the training group, we used a recursive partitioning technique to develop a simple predictive algorithm--infants were classified as high risk if head circumference was 31 cm or less or if chest circumference was 30 cm or less, and were classified as low risk otherwise. When tested in the validation group, this algorithm had sensitivity, specificity, and negative predictive value for prediction of preterm and LBW births above 90%. Thus, neonatal body measurements can be combined into a pragmatic, accurate screening tool suitable for clinical use in developing countries.

Effects of maternal age, parity, and smoking on the risk of stillbirth.

OBJECTIVE: To examine the effects of advanced maternal age, nulliparity, and smoking on risk of stillbirth as gestation advances, and to explore possible clinical mediators of these effects. DESIGN: A population based cohort study. SETTING: Sweden, 1983 to 1989. SUBJECTS: All singleton pregnancies of 28 weeks gestation or greater in Nordic citizens at least 20 years old (n = 638,242). MAIN OUTCOME MEASURES: Crude and adjusted risks of stillbirth; gestational age specific risks of stillbirth. RESULTS: Older women (35 years or older), smokers, and nulliparas had elevated risks of stillbirth. The elevated stillbirth risk in smokers was eliminated when women with intrauterine growth retardation, placental abruption, and placenta previa were excluded from the analysis. However, the higher risks in older women and nulliparas persisted even when the analysis excluded women with hypertension, diabetes, placental complications, or growth retardation. Over the course of the third trimester, the age related risk of stillbirth increased, the smoking related risk decreased, and the higher risk in nulliparas showed no clear trend with gestational age. CONCLUSIONS: The association between smoking and stillbirth is explained entirely by the higher incidence of growth retardation and placental complications in smokers. The clinical mediators of the associations of maternal age and parity with stillbirth remain unexplained. Gestational age is an important modifier of the effects of advanced maternal age and smoking on stillbirth risk.

Placental abruption. Maternal risk factors and associated fetal conditions.

OBJECTIVE: To investigate maternal risk factors and fetal conditions associated with abruption. METHODS: Prospective cohort study of 30,681 singleton pregnancies at least 28 weeks' gestation. Data collected by patient questionnaire at the first prenatal visit and by medical record review. RESULTS: 307 women had abruption (1%). After adjustment, important maternal risk factors included age (in years; OR 1.03; 95% CL 1.00, 1.06; p = 0.04) and less than 12 years of education (OR 1.58; 95% CL 1.10, 2.25; p = 0.01). Each pack of cigarettes smoked per day increased the risk by approximately 40% (OR 1.39; 95% CL 1.09, 1.79; p = 0.009). If abruption occurred, the perinatal mortality rate was substantially higher in women who smoked at least one pack per day than in nonsmokers (RR 2.53; 95% CL 1.14, 5.61; p = 0.02). Abruption was also significantly associated with intrauterine growth retardation and fetal malformations. The increased malformation rate was due entirely to nearly a five-times increase in congenital heart defects (OR 4.63; 95% CL 2.49, 8.55; p = 0.00000014). CONCLUSIONS: Heavier smoking increases the risk both of abruption and of perinatal death when abruption occurs. If the association between abruption and congenital heart defects is confirmed, early evaluation could lead to more prompt treatment of these malformations in infants delivered after abruption.

Dissociation of intracellular lysosomal rupture from the cell death caused by silica.

The relationship between intracellular lysosomal rupture and cell death caused by silica was studied in P388d(1) macrophages. After 3 h of exposure to 150 mug silica in medium containing 1.8 mM Ca(2+), 60 percent of the cells were unable to exclude trypan blue. In the absence of extracellular Ca(2+), however, all of the cells remained viable. Phagocytosis of silica particles occurred to the same extent in the presence or absence of Ca(2+). The percentage of P388D(1) cells killed by silica depended on the dose and the concentration of Ca(2+) in the medium. Intracellular lyosomal rupture after exposure to silica was measured by acridine orange fluorescence or histochemical assay of horseradish peroxidase. With either assay, 60 percent of the cells exposed to 150 mug silica for 3 h in the presence of Ca(2+) showed intracellular lysosomal rupture, was not associated with measureable degradation of total DNA, RNA, protein, or phospholipids or accelerated turnover of exogenous horseradish peroxidase. Pretreatment with promethazine (20 mug/ml) protected 80 percent of P388D(1) macrophages against silica toxicity although lysosomal rupture occurred in 60-70 percent of the cells. Intracellular lysosomal rupture was prevented in 80 percent of the cells by pretreatment with indomethacin (5 x 10(-5)M), yet 40-50 percent of the cells died after 3 h of exposure to 150 mug silica in 1.8 mM extracellular Ca(2+). The calcium ionophore A23187 also caused intracellular lysosomal rupture in 90-98 percent of the cells treated for 1 h in either the presence or absence of extracellular Ca(2+). With the addition of 1.8 mM Ca(2+), 80 percent of the cells was killed after 3 h, whereas all of the cells remained viable in the absence of Ca(2+). These experiments suggest that intracellular lysosomal rupture is not causally related to the cell death cause by silica or A23187. Cell death is dependent on extracellular Ca(2+) and may be mediated by an influx of these ions across the plasma membrane permeability barrier damaged directly by exposure to these toxins.